Method to identify genes associated with chronic myelogenous leukemia

ABSTRACT

A method to detect genes that are differentially expressed in chronic myelogenous leukemia is provided.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of the filing date of U.S. application Serial No. 60/248,403, filed Nov. 14, 2000, under 35 U.S.C. § 119(e).

STATEMENT OF GOVERNMENT RIGHTS

[0002] The invention was made with a grant from the Government of the United States of America (grants ROl-HL-49930 and ROI-CA-74887 from the National Institutes of Health). The Government may have certain rights to the invention.

BACKGROUND OF THE INVENTION

[0003] Chronic myelogenous leukemia (CML) is a lethal disease of hematopoietic stem cells, characterized by a specific chromosomal translocation between human chromosome 9 and human chromosome 22. The chromosome resulting from this translocation is commonly referred to as the Philadelphia chromosome (Darnell et al., 1990). The c-abl gene (ABL), a tyrosine kinase thought to be involved in growth control, resides on the distal arm of human chromosome 9, while the c-bcr gene (BCR) resides on human chromosome 22. The translocation places the promoter distal three exons of ABL, including those elements which encode the tyrosine kinase domain, downstream of either the first or second exon of BCR (Chung and Wong, 1995). The product of the translocation between human chromosome 9 and human chromosome 22 is a chimeric gene, BCR-ABL, which encodes a fusion protein, often referred to as p185^(BCR-ABL) or p210^(BCR-ABL), depending upon the inclusion of the second exon of BCR (Bartram et al., 1983). p185^(BCR-ABL) causes acute leukemia, typically lymphoblastic; p210^(BCR-ABL) usually causes CML, but can occasionally also cause acute leukemia.

[0004] Following the chromosomal translocation between chromosomes 9 and 22 within a single, primitive myeloid stem cell, the progeny of the affected cell gradually populate the entire intermediate and late hematopoietic maturational compartments. Despite the presence of the Philadelphia chromosome, these progeny, referred to as Ph⁺ cells, are able to differentiate and mature along the various myeloid lineages while retaining the capacity to function as their normal, unaffected counterparts.

[0005] Clinically, CML is characterized in its initial chronic phase by the circulation of malignant progenitors in the peripheral blood (Kantarjian et al., 1985). After three to five years, the disease transforms into a blast crisis, in which presumed additional genetic abnormalities prevent an early myeloid or lymphoid progenitor from differentiating (Clarkson and Strife, 1993; Daley and Ben Neriah, 1991; Deisseroth and Arlinghaus, 1991; Sawyers et al., 1991). In the chronic phase, the pool of malignant progenitors and precursors is also massively expanded (Kantarjian et al., 1985). It is thought that the massive expansion of the malignant cell population is partly due to decreased cell death (Cotter, 1995) and to the fact that, in contrast to normal progenitors (Clarkson et al., 1997; Verfaillie et al., 1997), CML progenitors are never quiescent and proliferate continuously.

[0006] Compared with the native p145^(ABL) protein, which is found mainly in the cell nucleus, p210^(BCR-ABL) is located exclusively in the cytoplasm (Verfaillie et al., 1997; Verfaillie, 1998). The tyrosine kinase function and F-actin-binding function of p210^(BCR-ABL) is significantly elevated compared with that of the native p210^(BCR) protein (Konopka et al., 1989; Verfaillie et al., 1997; Verfaillie, 1998). The increased kinase activity and cytoplasmic location of the BCR-ABL gene product are essential elements of its transforming abilities (McWhirter et al., 1991).

[0007] Several in vitro and in vivo studies demonstrate that the presence of BCR-ABL is necessary and sufficient for transformation (Daley et al., 1990). For example, the introduction of BCR-ABL cDNA into hematopoietic cell lines causes growth factor-independent growth in vitro and tumorigenicity in vivo. Moreover, transplantation of murine stem cells transduced with BCR-ABL cDNA causes a CML-like phenotype, and transgenic expression of BCR-ABL causes a syndrome with myeloproliferative or acute leukemia-type characteristics.

[0008] Although a causative role of p210^(BCR/ABL) for the pathophysiology of CML has been demonstrated in cell line models and animal transplantation models, the mechanism(s) underlying p210^(BCR/ABL)-mediated transformation and how it causes the characteristic features of CML remain unclear.

[0009] Clinical treatment of CML has remained essentially unchanged for many years. Treatment of Ph⁺ CML with intensive chemotherapy alone does not induce persistent cytogenetic remissions (Kantarjian et al., 1985). With the exception of marrow ablative chemotherapy and/or total body irradiation followed by allogeneic bone marrow transplantation, no effective cure has been developed for the disease. And although allogeneic stem-cell transplantation can be curative (Enright et al., 1997), this therapy is available to <40% of patients because the disease commonly affects patients over the age of 50 (Kantarjian et al., 1985). Autologous transplantation is being considered as an alternative therapy. There is evidence to suggest that a Ph⁻ state can be induced by this treatment strategy and that autografting might increase survival (Bhatia et al., 1997). Unfortunately, almost all patients will suffer leukemic relapse after autografting, partly because of disease persistence in the host after the preparative regimen (Pichert et al., 1994) and partly because of persistent disease in the graft (Deisseroth et al., 1994). Novel therapeutic approaches are therefore needed desperately.

[0010] What is needed is a systematic method to identify genes associated with p210^(BCR-ABL)-mediated transformation, e.g., so as to identify therapeutic targets other than p210^(BCR-ABL) for CML.

SUMMARY OF THE INVENTION

[0011] The invention provides a method for the differential isolation of nucleic acid sequences that are present in one nucleic acid population and not in another. The method is based upon employing a first population of cells which express a gene product that is associated with a particular phenotype or disease, and another (second) population of cells which does not express that gene product. The method comprises contacting nucleic acid from a first sample with nucleic acid from a second sample under hybridization conditions so as to form binary complexes. Preferably, the first sample comprises nucleic acid from cells which express a protein that is associated with malignancy, e.g., hematopoietic stem or progenitor cell malignancy, and the second sample comprises nucleic acid from cells which do not express the protein. Then a nucleic acid molecule is identified which is present in the first sample which is not present in the second sample. Preferably, the identified nucleic acid molecule is isolated and characterized.

[0012] In one embodiment of the invention, the first population of cells comprises a vector that encodes a first gene product such as a chimeric protein, e.g., p210^(BCR-ABL), p185^(BCR-ABL), p230^(BCR/ABL), TEL-ABL, PDGF-ABL, AML-ETO, PML-RARα, MDS/EV1 and the like. Preferably, the vector also comprises a marker gene which encodes a second gene product that is detectable. In this embodiment of the invention, the second population of cells preferably comprise a vector comprising the marker gene. Cells from each population that express the second gene product are selected or detected, e.g., by sorting in a FACS, and nucleic acid molecules are identified that are preferentially expressed in the first population. The identified nucleic acid molecules, e.g., isolated RNAs or cDNAs, are then characterized, e.g., by sequencing. Thus, the method of the invention can be applied to identify genes associated with disease. However, the nucleic acid molecules of the invention are not limited to those identified by any particular method.

[0013] To define if and how p210^(BCR/ABL) affects expression of downstream genes, subtractive hybridization was employed to identify transcripts that are differentially expressed in human CD34⁺ cells that express p210^(BCR/ABL) relative to human CD34⁺ cells that do not express p210^(BCR/ABL). Cord blood (CB) CD34⁺ cells were transduced with an MSCV-retrovirus vector containing either eGFP alone (eGFP) or BCR/ABL cDNA-IRES-eGFP (p210-eGFP). GFP⁺ cells were FACS selected (>90% purity), and subtractive hybridization performed between the two populations using the Clontech PCR-Select™ System. Seventy-nine cDNA clones that were expressed in p210-eGFP but not eGFP transduced CD34⁺ cells were sequenced and analyzed. Forty-one of the sequences did not encode a characterized human protein. Of these, at least 15 were closely homologous to expressed sequence tags (ESTs), at least 10 had homology to genomic clones for which no mRNA transcripts or proteins had been identified, while 1 sequence had no match in available genomic, RNA or protein databases. In addition, at least 22 sequences had significant homologies to known genes. These genes are involved in protein degradation, signal transduction, cell cycle regulation, and in RNA splicing. Interestingly, genes hypothesized to be downstream molecules for p210^(BCR-ABL), i.e., c-myb, c-KIT, c-rav and c-myc, were not identified by the method of the invention. The observation that 4 differentially expressed genes (SRPK1, Sty, Gu, SNRNP-G) are involved in RNA splicing is remarkable, and may provide an explanation for the finding that CML CD34⁺ cells and cell lines express a number of alternatively spliced proteins, including Pyk2, beta₁-B integrin, CSCP, and MPP1 (Verfaille et al., unpublished results; Deininger et al., 2000).

[0014] The invention also provides isolated nucleic acid molecules comprising nucleic acid segments encoding polypeptides that are expressed in cells that express a protein, e.g., p210^(BCR-ABL), that is associated with disease. For example, the invention includes isolated nucleic acid molecules comprising an open reading frame comprising any one of SEQ ID NOs:1-79, or the complement thereof, or nucleic acid molecules which hybridize thereto, e.g., under moderate and/or stringent hybridization conditions. Preferred nucleic acid molecules comprise an open reading frame comprising any one of SEQ ID NOs:1, 3-4, 11, 14-17, 19, 22, 25, 27, 29, 32, 35, 37-39, 41, 44-47, 52-54, 57-58, 60-62, 64, 67-79, the complement thereof, or nucleic acid molecules which hybridize thereto, e.g., under moderate and/or stringent hybridization conditions. Moderate and stringent hybridization conditions are well known to the art, see, for example sections 9.47-9.51 of Sambrook et al. (1989). For example, stringent conditions are those that (1) employ low ionic strength and high temperature for washing, for example, 0.015 M NaCl/0.0015 M sodium citrate (SSC); 0.1% sodium lauryl sulfate (SDS) at 50° C., or (2) employ a denaturing agent such as formamide during hybridization, e.g., 50% formamide with 0.1% bovine serum albumin/0.1% Ficoll/0.1% polyvinylpyrrolidone/50 mM sodium phosphate buffer at pH 6.5 with 750 mM NaCl, 75 mM sodium citrate at 42° C. Another example is use of 50% formamide, 5×SSC (0.75 M NaCl, 0.075 M sodium citrate), 50 mM sodium phosphate (pH 6.8), 0.1% sodium pyrophosphate, 5× Denhardt's solution, sonicated salmon sperm DNA (50 μg/ml), 0.1% sodium dodecylsulfate (SDS), and 10% dextran sulfate at 42° C., with washes at 42° C. in 0.2×SSC and 0.1% SDS.

[0015] The sequences of the nucleic acid molecules are useful as probes, to obtain full length sequences, i.e., a sequence that comprises an open reading frame that encodes a full length polypeptide, and in expression cassettes, as well as to prepare primers (oligonucleotides) for amplification or non-amplification-based methods to detect expression of the corresponding genes, e.g., using RT-PCR or linear amplification, in cells, such as in primary CML cells or CML lines, relative to normal cells.

[0016] Thus, the invention also provides probes and primers comprising at least a portion of the nucleic acid molecules of the invention. The probes or primers of the invention are preferably detectably labeled or have a binding site for a detectable label. Preferably, the probes or primers of the invention are at least about 7, more preferably at least about 15, but less than about 200, more preferably less than about 50, contiguous nucleotides bases having at least about 80% identity, more preferably at least about 90% identity, to the isolated nucleic acid molecules of the invention. Such probes or primers are useful to detect, quantify, isolate and/or amplify DNA strands that are related to the nucleic acid molecules of the invention.

[0017] Also provided is an expression cassette comprising an open reading frame comprising any one of the nucleic acid molecule of the invention operably linked to a promoter functional in a host cell, as well as a host cell, the genome of which is augmented with the expression cassette. Preferred host cells are vertebrate cells, e.g., mammalian cells. Further provided are isolated polypeptides encoded by the nucleic acid molecules of the invention.

[0018] The expression of partial or full length sequences corresponding to the nucleic acid molecules of the invention in sense or antisense orientation may be employed to further characterize the role of the encoded gene(s) product in diseased and/or in normal cells. Thus, overexpression or aberrant expression, e.g., expression which is spatially or temporally different, of one or more of the identified genes, may result in identifying the mechanism associated with transformation, e.g., p210^(BCR-ABL) transformation, and identifying other molecular target(s) for therapy. Once a target is identified, agents that interact with that target, including RNA or polypeptides, are employed to inhibit or prevent disease. For example, antisense sequences or ribozymes specific for the RNA target, or agents that bind to the encoded polypeptide and inhibit its activity, may be used to inhibit or prevent disease.

[0019] In a preferred embodiment of the invention, a PCR-based subtractive hybridization method is employed to identify genes, the expression of which is altered in cells that express a gene associated with hematopoietic stem cell malignancy. Those identified genes are useful as probes or primers to detect expression of those genes in malignant and normal cells, as well as therapeutic targets, e.g., via antisense expression or agents that alter the activity or amount of the encoded gene product.

[0020] Also provided is a method to identify an agent that inhibits or reduces the expression of a gene associated with hematopoietic cell malignancy. The method comprises contracting a cell or cell extract thereof with the agent, wherein the cell expresses a nucleic acid molecule comprising any one of SEQ ID Nos: 1-79. Then an agent is identified that inhibits or reduces expression of the nucleic acid molecule or the polypeptide encoded thereby. For example, the agent may a ribozyme, DNAzyme, antibody, e.g., a polyclonal, monoclonal, humanized or ScFv antibody, or antisense molecule. Preferably, the agent inhibits or reduces cell migration, cell proliferation, cell death or genetic instability, or increases cell adhesion.

BRIEF DESCRIPTION OF THE FIGURES

[0021]FIG. 1 shows a schematic of a method to identify a gene, the expression of which is altered in p210^(BCR-ABL) cells.

[0022]FIG. 2 depicts the sequence identifier number associated with each sequence identified by the method of the invention. A) Sequence identifier number associated with the genes identified in Example 1. B) Sequence identifier number associated with the known genes identified in Example 1. C) Sequence identifier number associated with the unknown genes identified in Example 1.

[0023]FIG. 3 shows the nucleic acid sequences identified by the method of the invention.

DETAILED DESCRIPTION OF THE INVENTION

[0024] Definitions

[0025] “Marker genes” are genes that impart a distinct phenotype to cells expressing that gene and thus allow such cells to be distinguished from cells that do not have the marker gene. Such genes may encode either a selectable or screenable marker, depending on whether the marker confers a trait which one can ‘select’ for by chemical means, i.e., through the use of a selective agent (e.g., a herbicide, antibiotic, or the like), or whether it is simply a “reporter” trait that one can identify through observation or testing, i.e., by ‘screening’. Of course, many examples of suitable marker genes are known to the art and can be employed in the practice of the invention. Screenable markers that may be employed include, but are not limited to, a β-glucuronidase or uidA gene (GUS), a β-lactamase gene, a β-galactosidase gene, a luciferase (luc) gene, an aequorin gene, a green fluorescent protein gene (GFP) gene, a blue, red or yellow fluorescent protein gene, a chloramphenicol acetyltransferase gene (CAT), horseradish peroxidase gene (HRP), an alkaline phosphatase gene (AP) and others. Thus, a “marker gene” is one which is detectable by spectroscopic, photochemical, biochemical, immunochemical, or chemical means. Preferred marker genes are those which are detectable without disruption of a cell, including genes that confer resistance to a chemical or drug.

[0026] Means of detecting labels are well known to those of skill in the art. Thus, for example, where the label is a radioactive label, means for detection include a scintillation counter or photographic film as in autoradiography. Where the label is a fluorescent label, it may be detected by exciting the fluorochrome with the appropriate wavelength of light and detecting the resulting fluorescence, e.g., by microscopy, visual inspection, via photographic film, by the use of electronic detectors such as charge coupled devices (CCDs) or photomultipliers and the like.

[0027] Similarly, enzymatic labels may be detected by providing appropriate substrates for the enzyme and detecting the resulting reaction product. Finally, simple colorimetric labels are often detected simply by observing the color associated with the label.

[0028] As used herein, the terms “isolated and/or purified” refer to ill vitro isolation of a RNA, DNA or polypeptide molecule from its natural cellular environment, and from association with other components of the cell, such as nucleic acid or polypeptide, so that is can be sequenced, replicated and/or expressed. For example, “an isolated nucleic acid molecule” of the invention is RNA or DNA containing greater than 7, preferably 15, and more preferably 20 or more sequential nucleotide bases that hybridize to the RNA or DNA corresponding to any one of SEQ ID Nos. 1-79, or the complement thereof, and remain stably bound under moderate or stringent conditions, as defined by methods well known to the art, e.g., in Sambrook et al. (1989).

[0029] A nucleic acid molecule which “hybridizes” to a reference nucleic acid sequence duplexes or binds to that nucleic acid. A nucleic acid molecule which “hybridizes” to a reference sequence can include sequences which are shorter or longer than the reference sequence. Typically, the DNA:DNA hybridization is done in a Southern blot protocol using a 0.2×SSC, 0.1% SDS, 65° C. wash. The term “SSC” refers to a citrate-saline solution of 0.15 M sodium chloride and 20 mM sodium citrate. Solutions are often expressed as multiples or fractions of this concentration. For example, 6×SSC refers to a solution having a sodium chloride and sodium citrate concentration of 6 times this amount or 0.9 M sodium chloride and 120 mM sodium citrate. 0.2×SSC refers to a solution 0.2 times the SSC concentration or 0.03 M sodium chloride and 4 mM sodium citrate. Accepted means for conducting hybridization assays are known and general overviews of the technology can be had from a review of: Hames and Higgins, 1985; Meinkoth and Wahl, 1984; Sambrook et al., 1989; and Innis et al., 1990.

[0030] “Moderate” and “stringent” hybridization conditions are well known to the art, see, for example sections 9.47-9.51 of Sambrook et al. (1989). For example, stringent conditions are those that (1) employ low ionic strength and high temperature for washing, for example, 0.015 M NaCl/0.0015 M sodium citrate (SSC); 0.1% sodium lauryl sulfate (SDS) at 50° C., or (2) employ a denaturing agent such as formamide during hybridization, e.g., 50% formamide with 0.1% bovine serum albumin/0.1% Ficoll/0.1% polyvinylpyrrolidone/50 mM sodium phosphate buffer at pH 6.5 with 750 mM NaCl, 75 mM sodium citrate at 42° C. Another example is use of 50% formamide, 5×SSC (0.75 M NaCl, 0.075 M sodium citrate), 50 mM sodium phosphate (pH 6.8), 0.1% sodium pyrophosphate, 5× Denhardt's solution, sonicated salmon sperm DNA (50 μg/ml), 0.1% sodium dodecylsulfate (SDS), and 10% dextran sulfate at 42° C., with washes at 42° C. in 0.2×SSC and 0.1% SDS.

[0031] “Denaturation” refers to the process by which a double-stranded nucleic acid is converted into its constituent single strands. Denaturation can be achieved, for example, by the use of high temperature, low ionic strength, acidic or alkaline pH, and/or certain organic solvents. Methods for denaturing nucleic acids are well-known in the art.

[0032] “Annealing” or “hybridization” refers to the process by which complementary single-stranded nucleic acids form a double-stranded structure, or duplex, mediated by hydrogen-bonding between complementary bases in the two strands. Annealing conditions are those values of, for example, temperature, ionic strength, pH and solvent which will allow annealing to occur. Many different combinations of the above-mentioned variables will be conducive to annealing. Appropriate conditions for annealing are well-known in the art, and will generally include an ionic strength of 50 mM or higher monovalent and/or divalent cation at neutral or near-neutral pH. An annealing mixture is a composition containing single-stranded nucleic acid at the appropriate temperature, pH and ionic strength to allow annealing to occur between molecules sharing regions of complementary sequence.

[0033] A “duplex” refers to a double-stranded polynucleotide.

[0034] “Amplification” is the process by which additional copies of a nucleic acid sequence or collection of nucleic acid sequences are generated. Amplification is generally achieved enzymatically, using a DNA polymerase enzyme. Current techniques allow exponential amplification of any sequence flanked by binding sites for a pair of oligonucleotide primers, through reiterative application of denaturation, primer annealing and polymerase extension steps, commonly known as a polymerase chain reaction. U.S. Pat. No. 4,683,202, Saiki et al., 1988; Innis et al., 1990; Ehrlich, 1989. Under the most widely-practiced conditions of the polymerase chain reaction, the rate of polymerization is approximately 1,000-2,000 nucleotides per minute. Accordingly, the maximum length of amplifiable sequence will be limited by the reaction conditions (for example, the duration of the extension step). The ability to control the extent of elongation in a polymerase chain reaction can be used to advantage to generate lower-complexity subsets of amplified fragments from an initial fragment collection of high complexity.

[0035] Nucleic acid molecules of interest in the present invention may be cloned or amplified, e.g., by in vitro methods, such as the polymerase chain reaction (PCR), the ligase chain reaction (LCR), the transcription-based amplification system (TAS), the self-sustained sequence replication system (3SR) and the Qβ replicase amplification system (QB). A wide variety of cloning and in vitro amplification methodologies are well-known to persons of skill. Examples of these techniques and instructions sufficient to direct persons of skill through many cloning exercises are found in Berger and Kimmel; Sambrook et al., 1989; Ausubel et al., 1994; U.S. Pat. No. 5,017,478; and European Patent No. 0,246,864.

[0036] A “polynucleotide”, “nucleic acid”, “nucleic acid molecule”, “nucleic acid sequence” or “nucleic acid segment” is a polymer of nucleotides, and the terms are meant to encompass both RNA and DNA, as well as single-stranded and double-stranded polynucleotides, as well as molecules containing modifications of the base, sugar or phosphate groups as are known in the art.

[0037] A “population” of polynucleotides, or nucleic acid molecules, sequences or segment is any collection comprised of different nucleotide sequences. Examples of polynucleotide populations include, but are not limited to, those which represent the genome of a normal cell, the genome of an infected cell, the genome of a neoplastic cell, the genome of a cell existing in a pathological state, the DNA that is characteristic of a particular cell, multicellular structure, organism, state of differentiation, pathological or non-pathological state, the total RNA population of a cell, the polyadenylated RNA population of a cell, or a cDNA population representative of the mRNA population of a particular cell, multicellular structure, organism, state of differentiation, pathological or non-pathological state. Using the methods of the invention, a sample population of polynucleotides comprising more than one different polynucleotide sequence is compared to a sample from a control population of polynucleotides to identify nucleic acid molecules that are unique to the sample population.

[0038] A “primer” is an oligonucleotide capable of base-pairing with a polynucleotide and serving as a site from which polymerization can be initiated.

[0039] An “oligonucleotide” is a short nucleic acid, generally DNA and generally single-stranded. Generally, an oligonucleotide will be shorter than 200 nucleotides, more particularly, shorter than 100 nucleotides, even more particularly, 50 nucleotides or shorter, but greater than 7 nucleotides, and preferably greater than 10 nucleotides, in length.

[0040] “Genomic” DNA is DNA obtained from a cell representing all or part of the genome of that cell.

[0041] cDNA or “complementary DNA” is DNA obtained from copying RNA by reverse transcription. It most often represents the population of mRNA molecules found in a particular cell, cell type, state of development or pathological state.

[0042] A “variant” polypeptide of the invention has at least about 80%, more preferably at least about 90%, and even more preferably at least about 95%, but less than 100%, contiguous amino acid sequence identity to a polypeptide having an amino acid sequence encoded by an open reading frame comprising any one of SEQ ID NOs:1-79, or a fragment thereof. A preferred variant polypeptide includes a variant polypeptide or fragment thereof having at least about 1%, more preferably at least about 10%, and even more preferably at least about 50%, the activity of the polypeptide having the amino acid sequence encoded by DNA comprising any one of SEQ ID NOs:1-79.

[0043] A “variant” nucleic acid sequence of the invention has at least about 80%, more preferably at least about 90%, and even more preferably at least about 95%, but less than 100%, contiguous nucleic acid sequence identity to a nucleic acid sequence comprising any one of SEQ ID NOs:1-79, or a fragment thereof. The amino acid and/or nucleic acid similarity (or homology) of two sequences may be determined manually or using algorithms well known to the art.

[0044] The term “sequence homology” or “sequence identity” means the proportion of base matches between two nucleic acid sequences or the proportion amino acid matches between two amino acid sequences. The term “sequence identity” means that two polynucleotide sequences are identical (i.e., on a nucleotide-by-nucleotide basis) over the window of comparison. The term “percentage of sequence identity” means that two polynucleotide sequences are identical (i.e., on a nucleotide-by-nucleotide basis) over the window of comparison. The term “percentage of sequence identity” is calculated by comparing two optimally aligned sequences over the window of comparison, determining the number of positions at which the identical nucleic acid base (e.g., A, T, C, G, U, or I) occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison (i.e., the window size), and multiplying the result by 100 to yield the percentage of sequence identity. The terms “substantial identity” as used herein denote a characteristic of a polynucleotide sequence, wherein the polynucleotide comprises a sequence that has at least 85 percent sequence identity, preferably at least 90 to 95 percent sequence identity, more usually at least 99 percent sequence identity as compared to a reference sequence over a comparison window of at least 20 nucleotide positions, frequently over a window of at least 20-50 nucleotides, wherein the percentage of sequence identity is calculated by comparing the reference sequence to the polynucleotide sequence which may include deletions or additions which total 20 percent or less of the reference sequence over the window of comparison.

[0045] Gaps (in either of the two sequences) are permitted to maximize matching; gap lengths of 15 bases or less are usually used, 6 bases or less are preferred with 2 bases or less more preferred. When using oligonucleotides as probes; the sequence homology between the target nucleic acid and the oligonucleotide sequence is generally not less than 17 target base matches out of 20 possible oligonucleotide base pair matches (85%); preferably not less than 9 matches out of 10 possible base pair matches (90%), and more preferably not less than 19 matches out of 20 possible base pair matches (95%).

[0046] Two amino acid sequences are homologous if there is a partial or complete identity between their sequences. For example, 85% homology means that 85% of the amino acids are identical when the two sequences are aligned for maximum matching. Gaps (in either of the two sequences being matched) are allowed in maximizing matching; gap lengths of 5 or less are preferred with 2 or less being more preferred. Alternatively and preferably, two protein sequences (or polypeptide sequences derived from them of at least 30 amino acids in length) are homologous, as this term is used herein, if they have an alignment score of at more than 5 (in standard deviation units) using the program ALIGN with the mutation data matrix and a gap penalty of 6 or greater. See Dayhoff, M. O., in Atlas of Protein Sequence and Structure, 1972, volume 5, National Biomedical Research Foundation, pp. 101-110, and Supplement 2 to this volume, pp. 1-10.

[0047] The following terms are used to describe the sequence relationships between two or more polynucleotides: “reference sequence”, “comparison window”, “sequence identity”, “percentage of sequence identity”, and “substantial identity”. A “reference sequence” is a defined sequence used as a basis for a sequence comparison; a reference sequence may be a subset of a larger sequence, for example, as a segment of a full-length cDNA or gene sequence given in a sequence listing, or may comprise a complete cDNA or gene sequence. Generally, a reference sequence is at least 20 nucleotides in length, frequently at least 25 nucleotides in length, and often at least 50 nucleotides in length. Since two polynucleotides may each (1) comprise a sequence (i.e., a portion of the complete polynucleotide sequence) that is similar between the two polynucleotides, and (2) may further comprise a sequence that is divergent between the two polynucleotides, sequence comparisons between two (or more) polynucleotides are typically performed by comparing sequences of the two polynucleotides over a “comparison window” to identify and compare local regions of sequence similarity.

[0048] A “comparison window”, as used herein, refers to a conceptual segment of at least 20 contiguous nucleotides and wherein the portion of the polynucleotide sequence in the comparison window may comprise additions or deletions (i.e., gaps) of 20 percent or less as compared to the reference sequence (which does not comprise additions or deletions) for optimal alignment of the two sequences. Optimal alignment of sequences for aligning a comparison window may be conducted by the local homology algorithm of Smith and Waterman (1981), by the homology alignment algorithm of Needleman and Wunsch (1970), by the search for similarity method of Pearson and Lipman (1988), by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package Release 7.0, Genetics Computer Group, 575 Science Dr., Madison, Wis.), or by inspection, and the best alignment (i.e., resulting in the highest percentage of homology over the comparison window) generated by the various methods is selected. Preferably, default parameters are employed.

[0049] As applied to polypeptides, the term “substantial identity” means that two peptide sequences, when optimally aligned, such as by the programs GAP or BESTFIT using default gap weights, share at least about 80 percent sequence identity, preferably at least about 90 percent sequence identity, more preferably at least about 95 percent sequence identity, and most preferably at least about 99 percent sequence identity.

[0050] Nucleic Acid Molecules of the Invention and the Polypeptides Encoded Thereby

[0051] The ability to identify nucleic acid sequences which are expressed in one nucleic acid sample and not in another is of intense interest in the field of molecular biology. The identification of differentially expressed nucleic acid sequences can provide valuable clues as to genetic bases for disease, inherited dominant and recessive traits, genetic alterations which give rise to diseases such as cancer, determining species similarities and differences, genotyping, and taxonomic classification.

[0052] The present invention relates to isolated nucleic acid molecules that are specifically or differentially expressed in cells which express a protein associated with disease. Thus, the expression of the nucleic acid molecules of the invention is induced by the protein associated with disease or are otherwise downstream of the expression of the disease-associated protein in a pathway that links the two. Exemplary nucleic acid molecules which are expressed in p210^(BCR-ABL)-expressing cells are described in FIG. 3. These sequences are useful as nucleic acid probes for hybridization assays and as primers, e.g., for use in amplification reactions. The present invention also relates to isolated polypeptides, as well as to methods for obtaining isolated polypeptides, e.g., by producing recombinant polypeptides, encoded by the nucleic acid molecules of the invention. The present invention also relates to antibodies which specifically bind to the encoded gene products, and methods of therapy for diseases, e.g., for ALL and CML and other types of cancer.

[0053] In one embodiment of the invention, over 50 different cDNAs were isolated and sequenced, the RNA of which is expressed in p210^(BCR-ABL) expressing cells. Exemplary nucleic acid molecules include RNA or DNA corresponding to any one of SEQ ID NOs:1-79, the complement thereof, or a variant thereof. Thus, this embodiment of the invention includes nucleic acid molecules comprising: a) the nucleotide sequence of any one of SEQ ID NOs:1-79 or a portion thereof; b) DNA, genomic or cDNA, comprising an open reading frame comprising any one of SEQ ID NOs:1-79, or the complement thereof, e.g., one which encodes a fill length polypeptide; or c) DNA which hybridizes to any one of SEQ ID NOs:1-79, the complement thereof, or a portion thereof, e.g., under moderate hybridization conditions. The nucleic acid molecules can be obtained from sources in which it occurs in nature (e.g., tissue or cell samples), from a DNA library, by means of recombinant technology or amplification procedures, or by synthetic techniques. Preferably, the nucleic acid source is mammalian, preferably primate, and more preferably human, DNA.

[0054] The nucleic acid molecules of the present invention can be antisense nucleic acid molecules. Antisense nucleic acid is complementary, in whole or in part, to a sense strand and can hybridize with the sense strand. The target can be DNA, or its RNA counterpart (i.e., wherein T residues of the DNA are U residues in the RNA counterpart). When introduced into a cell, antisense nucleic acid can inhibit the expression of the gene encoded by the sense strand. Antisense nucleic acids can be produced by standard techniques. In a particular embodiment, the nucleic acid molecule is wholly or partially complementary to and hybridizes with a nucleic acid having a sequence comprising any one of SEQ ID NOs:1-79.

[0055] Nucleic acids referred to herein as “isolated” are nucleic acids separated away from the nucleic acids of the genomic DNA or cellular RNA of their source of origin (e.g., as it exists in cells or in a mixture of nucleic acids such as a library), and may have undergone further processing. “Isolated” nucleic acids include nucleic acids obtained by methods described herein, similar methods or other suitable methods, including essentially pure nucleic acids, nucleic acids produced by chemical synthesis, by combinations of biological and chemical methods, and recombinant nucleic acids which are isolated.

[0056] Nucleic acids referred to as “recombinant” are nucleic acids which have been produced by recombinant DNA methodology, including those nucleic acids that are generated by procedures which rely upon a method of artificial recombination, such as PCR and/or cloning into a vector using restriction enzymes.

[0057] A nucleic acid molecule of the invention can be operably linked to one or more expression control elements (an expression cassette) which is incorporated into a vector, e.g., a viral vector, and the resulting construct introduced into host cells, which are maintained under conditions suitable for expression of the encoded polypeptide. The construct can be introduced into cells by a method appropriate to the host cell selected (e.g., transformation, transfection, electroporation, or infection). The encoded polypeptide can be isolated from the host cells or medium.

[0058] The nucleic acid molecules can be also used as probes to detect and/or isolate (e.g., by hybridization with RNA or DNA) variants or homologs (i.e., in other species) thereof, and/or to identify sequences corresponding to full length open reading frames. Moreover, the presence or frequency of the RNA corresponding to a nucleic acid molecule of the invention may be indicative of a disease.

[0059] The nucleic acid molecules of the invention are also useful for therapeutic purposes. For example, sense or anti-sense DNA fragments can be introduced into expression cassette which are subsequently cells in which expression of a particular nucleic acid sequence is to be reduced. The sense or anti-sense DNA fragments are expressed so as to result in reduced expression of the corresponding gene.

[0060] Pharmaceutical compositions which comprise nucleic acid molecules of the present invention and a suitable carrier (e.g., a buffer) are also the subject of this invention. The compositions can include additional components, such as stabilizers.

[0061] The present invention also relates to polypeptides encoded by the nucleic acid molecules of the invention, including a variant polypeptide which has at least 80% or more contiguous amino acid sequence identity to the polypeptide encoded by an open reading frame comprising a nucleic acid molecule of the invention, and which variant polypeptide has at least 1%, preferably 10% or more, of the activity of the non-variant (wild type) polypeptide, which can be obtained (isolated) from sources (e.g., cells) in which they occur in nature, produced using recombinant or genetic engineering methods or synthesized chemically. It also relates to pharmaceutical compositions which comprise the polypeptide and an appropriate carrier, such as a buffer. It may also comprise other components, such as stabilizers and other drugs.

[0062] Polypeptides referred to herein as “isolated” are polypeptides purified to a state beyond that in which they exist in cells in which they are produced. “Isolated” polypeptides include polypeptides obtained by methods described herein, similar methods or other suitable methods, including essentially pure proteins or polypeptides isolated from the source in which they occur, polypeptides produced by chemical synthesis (e.g., synthetic peptides), or by combinations of biological and chemical methods, and recombinant polypeptides which are isolated.

[0063] Polypeptides referred to herein as “recombinant” or “recombinantly produced” are polypeptides produced by the expression of nucleic acids encoding the polypeptides in a host cell which is modified to contain the nucleic acids encoding the polypeptide (e.g., by transfection with exogenous DNA which encodes the polypeptide) or is modified to express a gene which induces the expression of the nucleic acid molecules of the invention.

[0064] Another aspect of the invention relates to a method of producing polypeptide encoded by a nucleic acid molecule of the invention, a variant, or a fragment thereof. Recombinant polypeptide can be obtained, for example, by the expression of a recombinant DNA molecule encoding the polypeptide, a variant or a fragment thereof in a suitable host cell. Alternatively, recombinantly produced polypeptide is expressed in a suitable host cell by turning on or enhancing expression of a gene corresponding to the nucleic acid molecule of the invention present in (endogenous to) the host cell. Constructs suitable for the expression of the polypeptide or a variant can be introduced into a suitable host cell. Cells which express a recombinantly produced polypeptide or variant thereof, can be maintained in culture. Such cells are useful for a variety of purposes and can be used in the production of polypeptide for characterization, isolation and/or purification (e.g., affinity purification), and as immunogens, for instance. Suitable host cells can be prokaryotic, including bacterial cells such as E. coli, B. subtilis and other suitable bacteria (e.g., Streptococci) or eukaryotic, such as fungal or yeast cells (e.g., Pichia pastoris, Aspergillus species, Saccharomyces cerevisiae, Schizosaccharomyces pombe, Neurospora crassa), or other lower eukaryotic cells, and cells of higher eukaryotes, such as those from insects (e.g., Sf9 insect cells) or mammals, including humans (e.g., Chinese hamster ovary cells (CHO), COS cells, HuT 78 cells, 293 cells, hematopoietic cell lines, and the like), including cell lines and primary cells. See, e.g., Ausubel et al., 1993.

[0065] Host cells which produce recombinant polypeptide or a variant thereof can be produced as follows. A nucleic acid (e.g., DNA) encoding the polypeptide is inserted into a nucleic acid vector, e.g., a DNA vector, such as a plasmid, cosmid, phage, virus or other suitable replicon for expression. The resulting vector is introduced into a host cell, using known methods, and the host cell is maintained under conditions appropriate for growth of the host cell and expression of the endogenous DNA. For example, a nucleic acid encoding the polypeptide or a variant thereof can be incorporated into a vector, operably linked to one or more expression control elements, and the construct can be introduced into host cells, which are maintained under conditions suitable for expression of the polypeptide. The construct can be introduced into cells by a method appropriate to the host cell selected (e.g., transformation, transfection, electroporation, or infection). The encoded polypeptide can be isolated from the host cells or medium.

[0066] A variety of vectors is available, including vectors which are maintained in single copy or multiple copy, or which become integrated into the host cell chromosome. Suitable expression vectors can contain a number of components, including, but not limited to one or more of the following: an origin of replication; a selectable marker gene; one or more expression control elements, such as a transcriptional control element (e.g., a promoter, an enhancer, terminator), and/or one or more translation signals; a signal sequence or leader sequence for membrane targeting or secretion (of mammalian origin or from a heterologous mammal or non-mammalian species).

[0067] The present invention also relates to antibodies, both polyclonal and monoclonal, which bind the polypeptides of the invention in vitro and/or in vivo and, optionally, inhibit an activity or function characteristic of the polypeptide. The present invention further relates to pharmaceutical compositions which comprise anti-polypeptide antibodies and a suitable carrier, such as a buffer; they can also include further components, such as stabilizers. The antibodies of the present invention are useful in a variety of applications, including separation techniques, research, diagnostic and therapeutic applications.

[0068] In addition, antibodies of the present invention can be used to detect and/or measure the level of the polypeptide in a sample (e.g., tissue or body fluid) obtained from an individual (e.g., a human). For example, a sample (e.g., tissue and/or fluid) can be obtained from an individual and a suitable immunological method can be used to detect and/or measure polypeptide levels.

[0069] In an application of the method, antibodies which bind the polypeptide are used to analyze tissues or cells in mammals for reactivity and/or expression (e.g., immunohistologically). Thus, the antibodies of the present invention are useful in immunological diagnostic methods of assessing expression of the polypeptide in normal tissues or cells and cancerous tissues or cells.

[0070] Anti-polypeptide antibodies also have therapeutic uses. An anti-polypeptide antibody can be administered in an amount effective to inhibit the activity of the polypeptide. For therapy, an effective amount is sufficient to achieve the desired therapeutic and/or prophylactic effect. The antibody can be administered in a single dose or multiple doses. The dosage can be determined by methods known in the art and is dependent, for example, upon the individual's age, sensitivity, tolerance and overall well-being. Suitable dosages for antibodies can be from 0.1-1.0 mg/kg body weight per treatment.

[0071] According to the method, an antibody can be administered to an individual (e.g., a human) alone or in conjunction with another agent, which is administered before, along with or subsequent to administration of the antibody.

[0072] Compositions of the present invention can be administered by a variety of routes, including, but not limited to, parenteral (e.g., injection, including but not limited to, intravenous, intraarterial, intramuscular, subcutaneous; inhalation, including but not limited to, intrabronchial, intranasal or oral inhalation, intranasal drops; topical) and non-parenteral (e.g., oral, including but not limited to, dietary; rectal).

[0073] The formulation used will vary according to the route of administration selected (e.g., solution, emulsion, capsule). An appropriate composition comprising the nucleic acids, proteins or antibodies to be administered can be prepared in a physiologically acceptable vehicle or carrier. For solutions or emulsions, suitable carriers include, for example, aqueous or alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles can include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's or fixed oils. Intravenous vehicles can include various additives, preservatives, or fluid, nutrient or electrolyte replenishers. See, generally, Remington's Pharmaceutical Science, 16th Edition, Mack, Ed. (1980). For inhalation, the compound can be solubilized and loaded into a suitable dispenser for administration (e.g., an atomizer, nebulizer or pressurized aerosol dispenser). Nucleic acids, proteins and antibodies can be administered individually, together or in combination with other drugs or agents (e.g., other chemotherapeutic agents, immune system enhancers).

[0074] Methods for Identifying Differentially Expressed Transcripts

[0075] The invention in its broadest sense provides a method to identify genes associated with a particular phenotype, e.g., disease or malignancy, by identifying genes that are differentially expressed and so are associated with the phenotype. Methods for identifying differentially expressed transcripts, transcripts which differ in abundance between samples being compared, are known to the art.

[0076] The technical approaches used to compare RNA samples in vitro and identify differentially expressed transcripts, though being extremely diverse, all stem from the same origin: the method of differential hybridization or differential screening. Differential screening involves checking sequences (clones), picked at random from two libraries, for presence in one of the original RNA samples in higher concentration than in another. An enhancement of differential screening, called subtractive hybridization, enriches samples for differentially expressed transcripts prior to differential screening. Exemplary subtractive hybridization methods are described hereinbelow, although any other methods which identify differentially expressed genes may be employed to identify the nucleic acid molecules of the invention (e.g., see U.S. Pat. Nos. 5,726,022, 5,827,658, 5,958,738 and 6,066,457 and Matz et al., 1998).

[0077] For example, an alternative approach to differential screening is ‘differential display’ (DD). The basis of DD is as follows: (i) simplified pools of cDNA fragments (called subsets) are produced from the RNA samples being compared, their content being strictly defined by the intrinsic features of the protocol; (ii) the analogous pools obtained from the compared RNA samples are resolved side by side on a polyacrylamide gel (the produced band patterns are called fingerprints); (iii) fragments (defined by length) that are present in only one sample (or much more abundant in one than in the other) are excised from the gel and investigated; (iv) by changing the parameters of the pool generation protocol, other pools are produced and studied in a similar way to compare more mRNAs. The advantage of such an approach is that the abundance of several dozen randomly picked cDNA fragments can be checked simultaneously. Another important feature of DD is the ability to compare more than two RNA samples at once.

[0078] The methods of the invention may be employed with any source of nucleic acid in which one is interested in comparing for differences. The sources may be eukaryotic, prokaryotic, invertebrate, vertebrate, mammalian, non-mammalian, plant and others. Preferably, the source is a vertebrate source such as a mammalian source, e.g., from canine, bovine, murine, ovine, caprine, equine, and primates such as humans. RNA may be isolated by any known means as a subset of the genomic nucleic acid and subsequent synthesis of cDNA. It is also desirable to use cDNA as the first nucleic acid sample in assays in which cDNA or RNA is used as the second nucleic acid sample to prevent the isolation of products that are derived from intronic genomic sequences.

[0079] One subtractive hybridization method employs first and second nucleic acid samples that are separately subjected to at least one restriction endonuclease. The restriction endonuclease may provide for blunt ends or staggered (sticky) ends, usually staggered ends. It is preferred that both first and second nucleic acid samples are subjected to the same restriction endonuclease and that such endonuclease is one which recognizes and cuts at a four base site. For the subsequent steps it is further preferred that such restriction endonuclease be one which recognizes a four base sequence found within a longer six base or eight base sequence recognized by a restriction endonuclease. Almost 1500 restriction endonucleases are now known and at least 150 are commercially available. Complete lists plus details of restriction sites and reaction conditions are published, for example in Brown, 1991.

[0080] Once the first and second nucleic acid samples have been separately fragmented to produce first and second nucleic acid sample fragments, double-stranded oligonucleotide adaptors are ligated onto the ends of each of the strands of the fragments. The adaptor will usually be staggered at both ends, with one strand being longer than the other. The adaptors will generally serve to provide the sequence complementary to a primer to be used when a subsequent amplification step is employed. Thus, typically one end of the adaptor will be double-stranded and have one end complementary to the ends of the double-stranded nucleic acid fragments from the digestion, sometimes referred to herein as the proximal end of the adaptor. Each adaptor will preferably further contain a restriction site located distal to the proximal end.

[0081] The restriction site in the adaptor is preferably one which has a six or eight base consensus sequence, and most preferably is such a one that further contains a 3′ sequence that ends in a four base consensus sequence that has ends that are complementary to the same ends that are created by the six or eight base cutter that is adjacent and external to it. Examples of such restriction endonucleases include, but are not limited to, DpnII (′GATC); BglII (A′GATCT); BamHI (G′GATCC); Tsp509I (′AATT), EcoRI (G′AATTC) and PacI (TT′AATTAA).

[0082] It is preferred that the adaptors used for the first nucleic acid sample fragments contain a restriction site which is different than the one used in the adaptors for the second nucleic acid sample fragments. The adaptor may further optionally contain a ligand binding end. A ligand binding end is particularly important if the fragments will not be amplified. A ligand or ligand binding end is a molecule which binds to another molecule and so permits the physical or chemical separation of molecules which are physically linked to the ligand or ligand binding end, e.g., biotin binds to avidin or streptavidin and digoxigenin binds to anti-digoxigenin antibodies. It is preferred that the adaptor have one strand longer than the other to serve as a complement to primers if the fragments are to be amplified.

[0083] For example, in one embodiment only the first nucleic acid sample fragments will contain adaptors having a restriction site. The second nucleic acid sample fragments do not necessarily need to have adaptors or a primer used for amplification with a restriction site. If this embodiment is employed, the adaptors and/or primers for the second nucleic acid sample fragments will have a ligand binding moiety to enable capture of the second nucleic acid sample fragments.

[0084] Alternatively, it is possible to ligate the same adaptors onto nucleic acid of the first nucleic acid sample and the second nucleic acid sample if different primers are subsequently used to amplify the two sample populations so long as a restriction endonuclease site is encoded within the primers used to amplify the first nucleic acid sample fragments.

[0085] Additionally, the adaptor ligated onto the first nucleic acid sample fragments may have “non-nested” restriction endonuclease sites; e.g. 5′EcoRI-GATC3′, where the EcoRI site is external to an initial DpnII digestion site. This protocol is less preferred, however, because when the EcoRI site is subsequently targeted by the restriction endonuclease in order to release the homoduplex from its biotinylated adaptors, approximately {fraction (1/16)} of the cDNA molecules may contain an internal EcoRI site.

[0086] The first and second nucleic acid fragments may be separately amplified to enhance the assay, preferably by PCR or other methods, using primers containing a sequence complementary to the respective adaptors and a ligand binding end.

[0087] Thus, the second nucleic acid sample fragments and the first nucleic acid sample fragments may be amplified separately by adding appropriate primers complementary to the adaptors using PCR, typically for about 10-35 cycles, more typically about 20 cycles, depending upon the initial concentration of second or first nucleic acid sample fragments being amplified. For a general overview of PCR, see Innis et al., 1990; and U.S. Pat. Nos. 4,683,195 and 4,683,202. The adaptors do not need to be removed.

[0088] The amplified first and second nucleic acid sample fragments are combined under hybridization conditions such that the fragments hybridize together creating essentially several possible complexes: first nucleic acid/second nucleic acid matches, second nucleic acid/second nucleic acid matches, and first nucleic acid/first nucleic acid matches. It is preferred that the second nucleic acid fragments are present in excess of the first nucleic acid sample fragments to increase the probability that the first nucleic acid/first nucleic acid complexes are representative of nucleic acid not found in the second nucleic acid sample. For example, second nucleic acid sample fragments are combined with the adaptor-ligated first nucleic acid fragments, with the second nucleic acid sample fragments present in excess, usually at least 5-fold excess and less than 500-fold excess, preferably about 100-fold excess for the first cycle of hybridization. Hybridization will be allowed to proceed at high stringency temperatures, usually about 60°-70° C. Various buffers and salt concentrations may be used to adjust for the desired stringency as will be appreciated by those in the art.

[0089] The first nucleic acid/first nucleic acid complexes present in the combined first and second nucleic acid solution can be readily separated from the other complexes depending upon the ligand used. Most conveniently, all of the combined fragments will be subjected to a restriction enzyme which recognizes the site in the first nucleic acid sample adaptors which will effectively remove the ligand binding end from the first nucleic acid/first nucleic acid molecules and not from the others. Thus, by capture technology which will attract the ligand binding end of the second nucleic acid/first nucleic acid complexes, one can readily separate out the first nucleic acid/first nucleic acid complexes. The first nucleic acid/first nucleic acid complexes may be further amplified and isolated, by, for example, ligating new adaptors onto the ends of the molecules and amplifying by PCR.

[0090] It may be of interest to carry out the process more than once, where different restriction endonucleases are used. Different fragments may be obtained and result in additional information.

[0091] Any resulting unique first nucleic acid sequences (i.e. those not found in the second nucleic acid sample) can be used as probes to identify sites in the first nucleic acid sample which differ from the second nucleic acid source. For this purpose they may be labeled in a variety of ways. Desirably in order to obtain substantially homogeneous compositions of each of the first nucleic acid sample sequences, the first nucleic acid sample sequences may be cloned by inserting into an appropriate cloning vector for cloning in a prokaryotic host. If desired, the cloned DNA may be sequenced to determine the nature of the target DNA. Alternatively, the cloned DNA may be labeled and used as probes to identify fragments in libraries carrying the target DNA. The target DNA may be used to identify the differences which may be present between the two sources of nucleic acid.

[0092] The resulting target DNA will be greatly enriched. It may be used as a probe to identify sites on the first nucleic acid sample sequences which differ from the second nucleic acid. The target nucleic acid may be sequenced directly by PCR or it may be cloned by inserting it in a cloning vector for cloning into a host cell. The cloned DNA can be sequenced to determine the nature of the target DNA through the use of dot blotting or other procedure. It may also be labeled and used as probes to identify fragments in libraries carrying the target DNA. Sequences can be identified and cloned for sequencing. Comparative searches with sequences described in accessible libraries such as Genbank (National Center for Biotechnology Information, Natl. Library of Medicine, National Institutes of Health, 8600 Rockville Pike, Bethesda, Md. 20894); Protein Identification Resource (PIR, Natl. Biomedical Research Foundation, 3900 Reservoir Road NW, Washington, D.C. 20007; EMBL, European Molecular Biology Laboratory, Heidelberg, Germany) can aid in identifying the sequence.

[0093] In another substractive hybridization method, the genes are isolated from tumorigenic tissue or cells having a malignant or neoplastic phenotype, as well as from normal cells. Thus, the method entails substantive hybridization of two sets of cDNA, one provided from the tissue of interest and the other from normal tissue.

[0094] Any technique may be employed to produce the cDNAs, including any methods of purifying total RNA or mRNA and any primers. For example, primers for first strand synthesis can include polyT, “anchored” polyT, primers with restriction enzyme recognition sequences build-in, primers to complement a polyN tail created by the terminal transferase, where N stands for any one of the four nucleotides to be used. The polymerases can be any of the available and known polymerases. Either set of cDNAs could be maintained and amplified by cloning into a plasmid. A set of cDNAs from the normal tissue can serve as subtractor cDNA for annealing to cDNA from samples from multiple tissues of interest. Further variations and options would be readily apparent to one skilled in the art.

[0095] In a preferred embodiment, a double stranded adapter oligonucleotide (oligo) is attached to the ends of the cDNA set prepared from the tissue of interest. The oligo set is composed of two, at least partially complementary synthetic oligos. They are attached to the cDNA by a DNA ligase. The attachment can be preceded by creation of protruding ends on the cDNA by cleavage with a restriction endonuclease for which a recognition side was built-in on the cDNA ends by the choice of oligos used to create the cDNA set. In this embodiment, the oligo set to be attached is designed to create, after self annealing, complementary ends to the cDNA. Alternatively, the cDNA is made blunt-ended by enzymatic reaction, Klenow fragment by example. Then the oligo set would be ligated to the cDNA by a blunt-ended ligation.

[0096] In a preferred embodiment, the cDNA ends are made blunt-ended as described above and ligated to an adapter set which is blunt ended at least at one end. Preferably, the cDNA derived from the normal tissue is biotinylated. Again, this requirement can be achieved by any of a number of methods readily apparent to one skilled in the art. By way of example, but not limited to those examples, the biotin label can be incorporated into the cDNA starting with the synthesis of a second strand or can result from PCR amplification of a pre-made cDNA set. The label can also be introduced by PCR amplification or by “nicktranslation” of a cDNA set or by photobiotinylation.

[0097] The invention also includes a mixing of the two cDNA sets, derived from the tissue of interest and from the normal tissues, followed by denaturation and annealing. An excess of subtractor cDNA will increase the efficiency of annealing (and eventual removal, see below) of the sequences that are common to the two cDNA sets and are not present in the tissue of interest. The melting and annealing conditions are standard for such experiments and known to one skilled in the art. The annealing results in populations of hybrid cDNAs.

[0098] Magnetic spheres make the job of removal of biotin containing DNA easier. Thus, little biotin labeled DNA should escape untrapped, reducing the background levels of cDNA recovered from the subtractive hybridization. Streptavidin coated beads are available commercially. They are used by other to remove biotin labeled DNA, unlike the current disclosure that employs them within in a subtractive hybridization protocol.

[0099] The subtractive hybridization results in a cDNA fraction, hereafter called flow-through, enriched in cDNAs representing genes expressed in tumorigenic tissue or cells having a malignant to neoplastic phenotype, but not free of all other cDNAs. Initial analysis is sometimes facilitated by cloning the cDNAs of the flow-through. The cloning step itself is facilitated by first carrying out a PCR amplification of the flow-through cDNAs. Both of these steps can be accomplished by use of the previously described adapter set that can a) contain a restriction enzyme recognition site and b) one of the oligos in the set can be used as PCR primer. All these analysis employ standard molecular biology techniques and numerous options and shortcuts will be readily apparent to one skilled in the art. In either or both case, cloned flow-through cDNAs or direct sequencing, “single lane” dideoxy sequencing may suffice if the sequence is known. Sequencing reactions could employ as primer the same oligo described above as part of the oligo set.

[0100] Another analysis would be either a RT-PCR or Northern blot analysis. The chosen cloned cDNA(s) described above would be hybridized to equivalent amounts of nucleic acids, DNA and/or RNA, from both the tissue of interest and the normal tissue. The relative intensity of the bands would be compared spectrophotometrically and result in a estimate of copy number. To a person skilled in the art, variations and shortcuts will be readily apparent. For example, but not limited to this examples, one could use dot blots rather than gels and blotting, or one can incorporate a control hybridization with a probe not expected to hybridize to the gene, to standardize the amount of nucleic acids from the two tissues used.

[0101] The invention will be further described by the following non-limiting example.

EXAMPLE

[0102] Cord blood (CB) CD34⁺ cells (Zhao et al., 1999) were transduced with a MSCV-retrovirus vector containing either eGFP alone (eGFP) or BCR/ABL cDNA-IRES-eGFP (p210-eGFP). GFP⁺ cells were FACS selected (>90% purity), and subtractive hybridization performed between the two populations using the Clontech PCR-Select™ System, according to the manufacturer's recommendations.

[0103] The PCR-Select method requires only one round of subtractive hybridization to subtract and equalize cDNAs, combined with suppression PCR for efficient amplification of target molecules. This dramatically increases the probability of obtaining differentially expressed, rare transcripts. In contrast, traditional subtractive hybridization methods require a large amount of poly A⁺ RNA and the tedious separation of ss and ds cDNA fractions. For use as tester and driver, cDNA is synthesized from only 0.5-2.0 μg of poly A⁺ RNA prepared from the two types of tissue or cells under comparison.

[0104] A total of 79 subtracted cDNA clones were expressed in p210-eGFP⁺ but not eGFP⁺ transduced CD34⁺ cells. The cDNAs were between 400-900 bp in length. Forty-one of the cDNA sequences represent uncharacterized human proteins. Of these, at least 15 were closely homologous to expressed sequence tags (ESTs), at least 10 had homology to genomic clones for which no mRNA transcripts or proteins had been identified, while 1 sequence had no match in available genomic, RNA or protein databases. In addition, at least 22 sequences were identified that have significant homologies to known genes, which are involved in protein degradation, signal transduction, cell cycle regulation, and in RNA splicing. The observation that 4 differentially expressed genes (SRPK1, Sty, Gu, SNRNP-G) are involved in RNA splicing may provide an explanation for the finding that CML CD34⁺ cells and cell lines express a number of alternatively spliced proteins, including Pyk2, beta₁-B integrin, CSCP (chondroitin sulfate core protein), and MPP1 (human palmitoylated erythrocyte membrane protein).

[0105] The identified sequences and/or their full length genes are used as probes to detect expression patterns in normal and CML cells, and/or cloned into expression vectors. The identified sequences and/or their full length equivalent may also be used to prepare primers for RT-PCR analysis of the expression of these sequences in primary CML cells. Thus, gene expression analyses will lead to important new insights in the molecular mechanisms underlying CML and may identify critical targets for novel therapies for this disease.

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[0145] Zhao et al., Blood, 90:4687-4686 (1999).

[0146] All publications, patents and patent applications are incorporated herein by reference. While in the foregoing specification, this invention has been described in relation to certain preferred embodiments thereof, and many details have been set forth for purposes of illustration, it will be apparent to those skilled in the art that the invention is susceptible to additional embodiments and that certain of the details herein may be varied considerably without departing from the basic principles of the invention.

0 SEQUENCE LISTING <160> NUMBER OF SEQ ID NOS: 79 <210> SEQ ID NO 1 <211> LENGTH: 758 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(758) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 1 cactagtaac ggccgccagt gtgctggaat tcggcttagc gtggtcgcgg ccgaggtaca 60 tttggttaaa cattttataa aaattcaagc aaaatttaaa acacagccaa tttcaacatt 120 tctacaaatt taaccagcat tattttggtc aaatccacct ttagctgaat taatgagaac 180 aaggacaagg gacattgaag tattctcctc accacaatgg aggtttttct cactttccac 240 actgcatagc cactacatgg aaactcccag aatgatgagc aattcagtca tgctctacac 300 ttttcttttc aatgaaaagt gatgtatctt cttgttttgc ttttgacaaa atatgaacta 360 aatacaagtc tataataaca agaatccaag agtagctcat acacaagtca actatgtgta 420 tgtttttatt atttaaagcc caccattcag cttatctgtc taaagagatg ataacaaaca 480 atttgtttct ttttcactaa tggatactgg tgancagtca gtggttaaaa nagggaaggt 540 ccaagacagt tgttnttaat ccagtccatt gcccacattt aactttttca actttaagaa 600 ttttgctttt gcctttgcct aaaaagggna aaacttgtgg nagntaaacg gncaaaccct 660 ttggctttga aagttaatnc nggatgatcc aggttngtcc tggccangtt tctaaaagcc 720 cctggttttt atttgacgng ggccggtaat ccaaaggg 758 <210> SEQ ID NO 2 <211> LENGTH: 739 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(739) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 2 gtaacggccg ccagtgtgct ggaattcggc ttagcgtggt cgcggccgag gtacaggcgc 60 tggacagtat aggcatgcat ctccacacta ttagttatta actggattaa actggggact 120 gcatcatcac gaacataact tcctgccgtt gtcaaaacac gcataattgt gtctatatgc 180 catcgtttgg aaggtgcata cttttctgca gcaagaaaga ttccagatgc acagtctgct 240 ttaaattctg gctcacacga atccagaaaa taaagtaatt ctttcatcat gcctcggata 300 ttattcccat ttaccagggc aaaactcaat tccattgcac gccgttttat tgagacatcc 360 aaatctttaa gacagtccac aattgtgctt ctgtgcctct gtacctgccc gggcggccgc 420 tcgaagccga attctgcaga tatccatcac actggcggcc gctcgagcat gcatntagag 480 ggccaattcg cctatagtga gtcgtattac aaatcactgg gcgncgnttt acacggtngn 540 gactgggaaa ccctggngtc cccacttaat ngcntgnagn aaatcccctt tngccgnttg 600 gcgtaaaacg aaaaggcccc accgntcgct ttncaacagt tgccaccntg atggnaatgg 660 ccccccttga cgggcataag cgcggnggng gggggtaccc caanggaccg tcattgcagg 720 cctagcccgt ctttgtttt 739 <210> SEQ ID NO 3 <211> LENGTH: 823 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(823) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 3 agnnnnnnag gnnntnnnnn nnttnnnnnc nntctnggna ccnagctcgg atccctagta 60 acggccgcca gtgtgctgga attcggctta gcgtggtcgc ggccgaggta ctgtaattct 120 ttgattggga tagtggaaac tctagccaaa aaaaaaaaat gaacacagaa gtacagtaaa 180 taatatggtg aagtctaccc caatatccct agggtggttg tggttagggc tataacgtag 240 tatcaatatg aagatattac agcatgtatt taaaagcaat tgactattag gtatcagact 300 tagtgttatg atacatttgt ctaatgaaat gaaatctgtt ttcagaaata atctttaaat 360 acaatggaat ttattgagca tctactatta tatttcatcc atcactttta aattttttct 420 ttgggaggaa cacttataaa ctcatgatat ggataacaga cctgtggaaa ttaatgtaag 480 ccctaagcag cttagttaga cattgaatct aggtctgcct ctaccctgca gtctaccagn 540 tcaagtagct ttaccaggtc aagtccttan aaaataacca taaccatcca agggcagngc 600 agttattaac naggtgtncc tgcccggccg gccgttcgaa agccgaattt tgcaannttt 660 ccatcacact ggcggccgtt cgancatgca tttaaagggc caattcgncc tntgggngtc 720 gaatacaatc actggccgcg tttacaacgt cgngctggga aaacctngcg tncccantta 780 atcgcttggn cnatnccctt tcccagctgg ngaatancna aan 823 <210> SEQ ID NO 4 <211> LENGTH: 756 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(756) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 4 ctagtaacgg ccgccagtgt gctggaattc ggcttagcgt ggtcgcggcc gaggtacctc 60 tgacaatgaa gcctaaattg tttacgttgg agagggagtg ggagataagc taaagaatgt 120 gatttgtctt ccatttgaag ataccaggga aaagtcttgt caagtagcag gccaccggtg 180 tctagtgtag aggagacgat ttctgtcgat agagagcaaa gccagccagg caaacgaacc 240 cgtaagccgc ctgagggaca gacaggcata aaacctaatg aatgggtagg tagactttgg 300 gcaaggctaa ttgcagcaag ctgtgttcag ttccccggcc tctgttaagt agtcattttt 360 atacgatctg tcggagggaa gaggaaatag acccacacgg taaatgaact tgtggtgttt 420 agctaggaag tggagtttgc tctaagtagc tctggtagca agactccagg gagcacatgg 480 caggcggact catctgagta tctgtgctna nggagttgtg ttaactgttg aaacacttan 540 aaaattggtn tanaaaaaaa taccttnccc ggcnggccgt tcgaaagccg aatttttgca 600 natttccata cactggcggc cgttgacatg catntaaagg gccaattcnc ctatangagt 660 cgattacaat tnctggccgc ggtttacacg ttgggatggg aaaacctgcg tcccaactaa 720 ttgcttgggn natcccnttg ccactgctaa tacnaa 756 <210> SEQ ID NO 5 <211> LENGTH: 736 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(736) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 5 ggccgccagt gtgctggaat tcggcttcga gcggccgccc gggcaggtac attacatttt 60 atgaagggaa acaaagagtt aattacaaga tgcaaaaaga taagaaagag acaaactaca 120 gcgtgagtat tgttcagagg tagtaagtga gcactctaag ctacagaaca tgttgaaatt 180 ctattggttt gtatgagttc gcatgaggta ataaagctgt gttttgattg gtgggatgta 240 taaatactct tttnctacac tatatacaac actccagaga gcagggcctt ttgcagatgc 300 ccagaggacg tagcaaacct tgacaagtct gtgcagcacc cagtgcacac cgtaaaaccc 360 cagacggatc aatctcgttt tcacctctat cagcagcaag tatcttcgtc tctcagaaca 420 atctggatcc ataattttat taccgagcag actctggggc actggtgctt tcagagagag 480 aaacgatgct accagtcttt gactaattnt acataagaga tctgaaccca aacgtgcgag 540 gagnttttta accccaccat ctttaacngg gttggcaaac agttnttntt ccacctcctt 600 tgtgatttga aagaaagaca tccagtcagt atggaatntg caaaagtcaa ttaggngngg 660 ggatttgcat tgtttacggt gnggttanng ttttggcctg gccggaccct tagccgattt 720 gannatcatc cctgng 736 <210> SEQ ID NO 6 <211> LENGTH: 769 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(769) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 6 gagctcggat ccactagtaa cggccgccag tgtgctggaa ttcggcttag cgtggtcgcg 60 gccgaggtac ccaatgaagg atccgatgaa tggctggcca gttactcaga gtaatatgtt 120 tatgagttaa atggattgca taacggcacc acttttcctt tgtcactgtg gtggataaat 180 gacaaagtag attccaatct cctgtataga aaggtggtta cccaatagcc tcactggtgg 240 cttgctagca gagcctcaag ttgcacctct gtggctttct gtaaattcga gtcctacagc 300 cacttcgaga acgctgcaat ccccaaggcc cacttggtcc atgctgaaga agcggctgtg 360 accccaatcc tgcctctctt ttgctcttca gtattactta ctggaggaat atgtaatatt 420 ctaggtcaag tctaggagag gctcatccta aaaaaaaaat tgcaaagtct tttctcaatt 480 aaaacaaaaa aagcctcaag tacctgcccg gcgggcgctc gaagcccnaa tnttnagata 540 ttcatacaat tgcnggcggt tgagccttgc ttttagangg gccaaattgg ccctatagng 600 ngtngantac aattcactgg ccggcgttta caacgtcnng actgggaaac cccggggttn 660 cccacttaat nccttgagga natccccttt ntcngctggn gtaaaacnaa aaggcccacc 720 gntgcctttc canaatgccc acctatggga angacccccc ttacggcnt 769 <210> SEQ ID NO 7 <211> LENGTH: 817 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(817) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 7 gnnnnnntnn nagnnnnntt nnnnnttnnn tnnnngctng gtaccgagct cggatccact 60 agtaacggcc gccagtgtgc tggaattcgg cttagcgtgg tcgcggccga ggtactcagt 120 gtaaggctat tatcgttttt catacataaa attttctagc tctgtaacac aatgcaattt 180 ttaatccatt caagtaagtt caaccccaaa gttgccgctt cccagcatta agacatgcac 240 ccacccctct tctaagattt tctaaaactt gtatttcggg gagaaagacc tcttttaaaa 300 aataatccca attagtggga gagtaaatgg ctgacattag tagcaaaacc ttagttatct 360 gaaaataaca tattggaaat gagacattat taggatttta aacaaacaat agcatttaga 420 cataaagtag gaagcaaaat acagtaaaca gaaatagtgt agccaaatat gcattctctt 480 cagctacact agagtggacc ttgcttagta cctgcccggg cgggcgctcg aaagcccgaa 540 ttctgcagat ttcatcacac tggcgggcgn ttcancctgc atttagangg gcccattcgc 600 cctntagggg ggtcgtattc aaatcactng ccgcggttta caaccgtcgn gactgggaaa 660 accctggggg ttcccactta atcgccttgg agcacatccc ttttggcagc tggngtatan 720 cgaaaggccc gaccgacgcc ttncaacnnt gcncacctga aggngaagga cccccctgta 780 nggnncntaa cgcggggggg nggggtnccc ncggnct 817 <210> SEQ ID NO 8 <211> LENGTH: 755 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(755) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 8 cactagtaac ggccgccagt gtgctggaat tcggcttagc gtggtcgcgg ccgaggtact 60 acatctgagg attccttggt cctttacaat agagtggctg ttcaaggaga tgtggttcgt 120 gaattaaaag ccaagaaagc accaaaggaa gatgtagatg cagctgtaaa acagcttttg 180 tctttgaaag ctgaatataa ggagaaaact ggccaggaat ataaacctgg aaaccctcct 240 gctgaaatag gacagaatat ttcttctaat tcctcagcaa gtattctgga aagtaaatct 300 ctgtatgatg aagttgctgc acaaggggag gtggttcgta agctaaaagc tgaaaaatcc 360 cctaaggcta aaataaatga agctgtagaa tgcttactgt ccctgaaggc tcagtataaa 420 gaaaaaactg ggaaggagta cctgcccggg cggccgctcg aaagccgaat tctgcagata 480 tccatcacac tggcggncgc tcgagcatgc attntagang gcccaattcg ccctatagtg 540 agtccganta caattcactg gccgcggttt acaaccgtcg tgactgggaa accctggcgt 600 tacccaactt aattgccttg ngcacatncc cctttcgcca gttgcgtaat ancnanaggn 660 cccaccgncc ccttccacaa ttcccacctg atggnnatgg ncccccctta cgggcataag 720 cccggggggt gnggttccca aggnaccctc cttct 755 <210> SEQ ID NO 9 <211> LENGTH: 766 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(766) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 9 tcggatccct agtaacggcc gccagtgtgc tggaattcgg cttcgagcgg ccgcccgggc 60 aggtacttat ctggcagcac tgagatgctc agttcaaatt cttggccatc ctgaaagggc 120 atgttcttgg attccacctg ctgcttccag gccccatact cacggctgtt catgaccaca 180 cgacgaccaa agcacacttg gaaatggaag acaatgtctg attcctcctt catctcagtg 240 tggaaatcca cctgcagata tggttcattc aagaaacaga caagtggtcg ccctttgatt 300 gtcacagtag aaccagtaga caaagaggca gcctctgtgt atggcacggg tagcagggac 360 attgttgtct ccttctgggt ggctcttctg aattgtgtcc agacttcccc gcgtacctcg 420 gccgcgacca cgctaagccg aattctgcag atatccatca cactggcggc cgctcgagca 480 tgcatntaga gggcccaatt tcgcctatag tgagtcgtan tacaattcac tggccgtcgt 540 tttacaacgt cgngactggg aaaaccctgg cgttcccaac ttaatcgctt gaacacatcc 600 ccttttcgcc agttgngtaa taacgaaana ggcccgcacc gncgcctttc caacagtgcn 660 cancctgaat ggcgaatgga cccccctnta gcgggcatta aacgcggggg tgtggtggta 720 cnccanngtn accgttcant tgcaggccta nnccgtcntt tntttt 766 <210> SEQ ID NO 10 <211> LENGTH: 743 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(743) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 10 ctagtaacgg ccgccagtgt gctggaattc ggcttagcgt ggtcgcggcc gaggtacctt 60 agctgtgagg ggggctgctg aaggcatgga ggacagtaat gacggctgtg cctccttgga 120 tggtggagac ctcagaaatg gtctgcaaca caggcactag gtcagtttcc cgcccttagc 180 tgaatgcaga tggatgctgg gagatggaca tggtgagatg gtgtggggag gatgttagaa 240 agctggaggt gtttatcact tctcaaggag ctctgaatat agggggaaaa aaacaacaaa 300 aaaaagccca gggagaaagc accattaagg atatacctat gccagcttct atagctgcac 360 ctgctttatt ggcaggtcac ttgccacaat tgcatctgcc ctctaaactt tttaattttc 420 acactgtatc ctagacatga atgcataaaa tacagtgtct ggcgggataa tgcagagagg 480 tcctgcccgg gcggccgcaa gcccgaattc tgcaagatat ncatacactg gcgggccgtt 540 cgacatgcat ttagaggccc aattcgccct atagtgagtc gnntacaatt tactgccncg 600 ttttacaacg tcgtgactgg naaaccctgc gttacccact taatcgnttg nagnnatccc 660 ntttnccagt tgctatagcn aanagccccn cgncgccttc caacattgtc acttatggga 720 tggaccccct tacggncata acc 743 <210> SEQ ID NO 11 <211> LENGTH: 825 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(825) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 11 agnnnnagnn nnnagnntnn nnnnnttnnn ncnnnctngg accggctcgg atccactagt 60 aacggccgcc agtgtgctgg aattcggctt agcgtggtcg cggccgaggt acaagtgaaa 120 tatttaaata ggaatctgaa acaaaacgaa ttcaatctga tcaaatccac aattaattga 180 agttttcatt ttattcaatt gtgaataaaa tagcagacac tgtttcatcc aataagccaa 240 tgatatcagc ttaggagaaa tgatctgcct ggcttgtgca agacaagaac agttaccttc 300 tgctgaaagg atgtgagttt tcaaatttgg ttttcatgtc atagtttcca aataaatgaa 360 ccgctccacc aaaaacgaca gtctagttgc tacctatctt ccagggtttc atcatacagc 420 catttataag cacaatcttt ggaacgctct atagtttcaa aaagtgtttt gaagtcttga 480 gggtgcatgt taactacttt ctcatcctcc tgttttccta tttgcatcaa tatatctctc 540 gcatcaaggn ggagtcaatg aaccgtaagt ggtctattac aggtgggcgc tgcgccctcc 600 cgaaacaagt gctttaacaa ggtgaaaaaa tatntttngn tcatanggng tnaggtcttg 660 gnaaataaat tttgacgagg aatcatttga ataananaca gcttttngtn gnaattggct 720 aanaattccc tacncttngg gtttccaccg gnccttccgg tgttntttna aatgatgcca 780 ngctcatggg cgaacctaat ctccaagtaa tgccagnnac nctna 825 <210> SEQ ID NO 12 <211> LENGTH: 761 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(761) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 12 tcggatccct agtaacggcc gccagtgtgc tggaattcgg ctttcgagcg gccgcccggg 60 caggtacatc tccggtgtcc ctgggacagg gaagactgcc actgttcatg aagtgatacg 120 ctgcctgcag caggcagccc aagccaatga tgttcctccc tttcaataca ttgaggtcaa 180 tggcatgaag ctgacggagc cccaccaagt ctatgtgcaa atcttgcaga agctaacagg 240 ccaaaaagca acagccaacc atgcggcaga actgctggca aagcaattct gcacccgagg 300 gtcacctcag gaaaccaccg tcctgcttgt ggatgagctc gaccttctgt ggactcacaa 360 acaagacata atgtacctcg gccgcgacca cgctaagccg aattctgcag atatccatca 420 cactggcggc cgctcgagca tgcatctaga gggcccaatt cgccctatag tgagtcgtat 480 tacaattcac tggccgtcgt ttacaacgtc gtgactnggn aaaccttggc gttncccaac 540 ttaatcgcct tgangacatn cccctttcgc cagctggcgt aatagcgaag aggccgcacc 600 gatcgccttt ccaacagttg cgcancctga atggggaatg gacgcgcctg taccggccat 660 taacgcggng ggtgnggngg ttcccncagg tgaccgttca nttgcagngc ctacgnccgt 720 ctttngtttt ttcttctttt tgccgttgcc ggtttcccgt a 761 <210> SEQ ID NO 13 <211> LENGTH: 766 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(766) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 13 ggtaccgagc tcggatccct agtaacggcc gccagtgtgc tggaattcgg cttagcgtgg 60 tcgcggccga ggtacgcggg acactcgctt ctggaacgtc tgaggttatc aataagctcc 120 tagtccagac gccatgggtc atttcacaga ggaggacaag gctactatca caagcctgtg 180 gggcaaggtg aatgtggaag atgctggagg agaaaccctg ggaaggctcc tggttgtcta 240 cccatggacc cagaggttct ttgacagctt tggcaacctg tcctctgcct ctgccatcat 300 gggcaacccc aaagtcaagg cacatggcaa gaaggtgctg acttccttgg gagatgccat 360 aaagcacctg gatgatctca agggcacctt tgcccagctg agtgaactgc actgtgacaa 420 gctgcatgtg gatcctgaga acttcaagct cctgggaaat gtgctggtga ccgttttggc 480 aatccatttc ggcaaagaat tcacccctga ggtgcangct tnctggcaga agatggtgac 540 tggagtgggc agtgncctgt ccttcanata ccacttgagc tcacttgcca tgatgcaaaa 600 ctttcaagga taggctttat tntgcaagca atcaaataat aaatctnttn tgtnaaaaaa 660 aaaaaaaaaa aaaaaaaaag tccttgccgg cggccgtcaa accgaatttg anattcatac 720 atgngggcgt cacatcatta aaggccaatc nctnanggtg nttaaa 766 <210> SEQ ID NO 14 <211> LENGTH: 732 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(732) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 14 ggccgccagt gtgctggaat tcggcttagc gtggtcgcgg ccgaggtaca cagattttaa 60 aagcattttt taaatttatt tttatttttt ccagattttt ttaggatata attgacaagt 120 aaaaaatgaa tatatttaag gtgcacaatg cgatgttttg gtatacgtgg acattgtgaa 180 gtggttgcaa caattaagtt aaataacata tctgtcacct cacatagtta cctttgtgtg 240 tgtgtgtgtg tgtttgatga gcataaaatc tatctagcag caaaggcatt ttctaaagtc 300 cagaaaatgc cactaatata tgcattaata atatacaaaa aaccagtaac taactttatt 360 atgttaattt atcttttctt ttctctgntg aactatttat ttacatacct aaactctact 420 caaactgctg ttgtnaaaaa caaggaggaa ttagtttctc ttnatctcta acaccagaag 480 aagatccatt ttgnagtctt attgctctgn tgaatgactg tctcctggtt tgnggcagac 540 tggaagcaag agtctntctg tttggccaca gtcctgcccg ggcgggcgtc gaaagcccga 600 atttgcagat tccatcnact ggcggccgtc gagctgcttt agagggccaa ttcgccttag 660 ggaggggata caatcactgg cgcgtttcac gcgggctggn aacctngggt nccactaatt 720 gctgaccatc cn 732 <210> SEQ ID NO 15 <211> LENGTH: 754 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(754) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 15 tcggatccac tagtaacggc cgccagtgtg ctggaattcg gctttcgagc ggccgcccgg 60 gcaggtacct tacttagcag agcactttgc aaacatatta cttattagca gagctctttg 120 tagaccttcc acatctggct gtcagatctt aaggttgtga atttaggctc cagttatatt 180 cactggagag cataatccca cacgggttat ttataaatac agagcctctg attggacggg 240 ctcctgccaa gaactagtaa tacccttgtt ttaaaatctt cacaaggtaa gacttaaaaa 300 gccaaccaaa caaattgctc tccattctac ttttaattgg gccaaacagc atatgctaca 360 gtagtaacat gtttttcgga gagtgtaaaa aactctgttt acatttgcct cctccgtggg 420 ttgatcgaaa atgtataaaa ctgactgctt ctcgccagcc tcagacaaga aagagtgagt 480 tgctggtcct cggccgcgac cacgctaagc cgaattctgn agatatncat cacactggcg 540 ggncgntcga gcatgcatnt agagggccaa ttcgncctat agtgagcgta ttacaattca 600 ctgggcgcgn tttacaacgt cgggctggga aaccctggcg ttcccactta atcgctgnag 660 nacatccctt tgcagtgggg taaaacgaaa ggccgacgat gncttccaac attgccanct 720 gatgggaatg gcnccctnag cgncataacg cggg 754 <210> SEQ ID NO 16 <211> LENGTH: 753 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(753) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 16 ctagtaacgg ccgccagtgt gctggaattc ggctttcgag cggccgcccg ggcaggtacc 60 aaccaaaatc tcgtattggc agatcttgac aggctggacc tgcaagatgt gacttgaatt 120 ttaaccattt attacataat ctctagtgat catgcatcta gttatcataa gaaataattt 180 aaaaggtttt gttgctgaaa gcagtaagtg gtgcagtaaa atacttaagt tattcaaaga 240 atgttatctt tcttgcaaga gtaatttaag cacatgggaa agattctaga ctttttgttt 300 cttgcaacaa cagtgccctc tgctgctaga aacctttttc tacttactat catttttatt 360 gtggcttgag ctcagtcaat ctggtgcaga tgaggctgga caactactaa ccaataaaat 420 caggagtttg tacctcggcc gcgaccacgc taagccgaat tctgcagata ttcatcacac 480 tggcgggcgc tcgagcatgc atttaagagg gcccaattcg cctatagtga ggcntattac 540 aaattnatgg ccgtcgtttt acaccgcgtg gntggggaaa accctggcgg tacccaactt 600 aatggnttgg agaacattcc ccttttcgcc anttgggtaa tacccnaaag ggccccaccg 660 atcgcctttc caacatttgc ncacctgatg gnaatggncc ccccttacgg gcattaagcc 720 ggggggtgtg gnggtccccc acggncntcc ttn 753 <210> SEQ ID NO 17 <211> LENGTH: 744 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(744) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 17 ctagtaacgg ccgccagtgt gctggaattc ggcttagcgt ggtcgcggcc gaggtactcc 60 aacaagacat gcataccatt ggtgcctaag atttttttac agttgtgttt ttatacagaa 120 attctttgta gaaattacta ttttttgtta aagattgttt atatgcttac aaagatttct 180 caggaagaca gcagagcaga ggaatctata tagatgtatg cacagacctg tctgtatgct 240 gaactttgtt aaaaatatct gccagttatt aaaaagcaca gtttaaatgg ggtggggtta 300 aagttcaggt aagtaagtta gagagaaaac attgtatgat cagctcctgc acttgatcta 360 tctttggctt cccaaacagt aactcactcc aggccaagtg tgccttagca cgagtgacca 420 cagtttaata gaccacacac atcgtttaaa cctgctcttg gtcattggna attacactga 480 acaaagtgca attactgnng aacagtttat ttttattaaa accttgnctg acaaaagggg 540 ncctcacatt gtngaccctg ggngccctac anaggntagc cttttcttta aggnttaacc 600 nggggctggt ggtttttttt ttgaaagagt taaggncnaa aattaatttg tngttgnnaa 660 aaaaaaaatt ccgtctttcg gntgantgnt ttgcangtca naaaaangga cctgccnggn 720 ggcgtnnaac caatttggaa ttcn 744 <210> SEQ ID NO 18 <400> SEQUENCE: 18 000 <210> SEQ ID NO 19 <211> LENGTH: 763 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(763) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 19 ctagtaacgg ccgcagtgtg ctggaattcg gctttgagcg gccgcccggg caggtacagg 60 aagcacacct tgatactgag gccatttaga gcaatttgtt taatgagtgg gttcagccat 120 caccaccagt ggccacctgt tcaataaaat tgcctagcac cacagtggga gagtcatcta 180 caccccaagg tgagctgtaa gactggccaa ttctttgaag accttttttc tgttgggaga 240 atggaaagca gaaagggaag ccaggctctt taatgttcca agtcaagctg tgcctcacac 300 aaggctctct ttttagctac taagtaacat actcaagact ttgtatctgt gcagcatttt 360 atggaaatca ctggtgacct ataggatatt actaaattat ttcaatagct ttattttttt 420 cctactttgg attctaggtg ggcattacag agttgaattc ctcactaccc ccttcccgtg 480 tcatttgttt attggaaact catgttacta gagnggtccc ngggccggan cacnctaagc 540 cgaattntgg agntttcata cactggnggc cgtttancat tcnttanagg gccaattcgc 600 cctaaanggg ncgtttcaaa ttactggccg gggttacaac ngnggatggg aaacccgggg 660 tcccaantaa tncctggaga aatccctttn cagtgggtaa acgaaaggcc ccnccgtcnc 720 ttccaaaatt gccacctnat ggatngcccc ccttaggcat aan 763 <210> SEQ ID NO 20 <211> LENGTH: 800 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(800) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 20 tnnttntnnc cnnctcgnat ccctagtaac ggccgccagt gtgctggaat tcggcttcga 60 gcggccgccc gggcaggtcc tctgtgataa acaatgaaaa gctgtctcca tgtcctgcca 120 ttgacaccac aggtccagca aggcttgnat cctctttttg acccctccaa tagtaaacaa 180 tcgaagaagc agggcactag tagcggcagc agcccatcct tgaccgagac atatggcttc 240 aatatcctca ttctgaggca agtctattat ccactctttg cttgaatccc aagaactaaa 300 gtgcaggcag tgaagcttgc ttgctagttc atcaagtgct ttcacatgcc aacaaaataa 360 gcttcgtggg aaagatctgc tattgtataa ttcaaagtgt ttgataagtg tgttgcatgg 420 tgttggaggt atcatggaac tcccatctat ggcattgtct tgctcatcat tatagcagcg 480 aattaattcc aatagagttc ccaccatgaa tctntgagtg gagatgcaac ngngttnaac 540 ctnactngaa atngnttttt ncccgggagg tggggattgg nnccntataa aaaggccttt 600 nggannttcc aaggggnaat tgggaatgct cctttttgcc attttcctct ccttttggaa 660 aaactngacc nntttttnna ttgaaantaa acngggttnt ttnantttta ggatggactt 720 tgtgtttngg ccaccgannc nnanangctc aaaaacnant nnttttaanc cctttgaaaa 780 aanggactcc ctgttnctta 800 <210> SEQ ID NO 21 <211> LENGTH: 777 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(777) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 21 ctagtaacgg ccgccagtgt gctggaattc ggctttcgag cggcncgccc gggcaggtac 60 gcggggacat ttgcttctga cacaactgtg ttcactagca acctcaaaac agacaccatg 120 gtgcatctga ctcctgagga gaagtctggc cgttctgccc tgtggggcaa gggtgaacgt 180 gggatgaaag ttggtgggtg aaggcctggg caaggctgct ggtgggtcta ccctttggac 240 ccagaggttc tttgagtcct ttggggatct gtcactcctg atgctgttat gggcaaccct 300 aaggtgaagg ctcatggcaa gaaagtgctc ggtgccttta gtgatggcct gctcacctgg 360 acaacctcaa gggcaccttt gccacactga gtgagcttgc acttgtgaca agctgcaccg 420 tggatcctga gaacttnagc tcctgggcaa cgtgctgntc tgtgtgctgg nccatcactt 480 tggcaaagaa ttaacccaca atgcangctt gctattaaaa aagngggggg tngtgnngnt 540 taatggccct ggccccnaat ttaactaaac ttnntttttt gttngccaaa tttttttnaa 600 aggttcnttt ttncctaagc caactnctaa nttgggggnt ttttnaaggc cttnncattt 660 ggntttccta nnaaaaaatt tttttttttt aaaaanannn nnnanntaaa atcctggcgg 720 acnccctagc catttganat tnannaaatg gggctttgga anttttangg gcaatnt 777 <210> SEQ ID NO 22 <211> LENGTH: 835 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(835) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 22 ggccgccagt gtgctggaat tcggctttcg agcggcncgc ccgggcaggt acaaggtgaa 60 atatttaaat agggaatctg gaaaccaaaa acgaattcaa atctggatcc aaaatcccac 120 aattaaattg gaaggtttca atttttattc aaattggtga ataaaaatag cagaccactg 180 gtttcatcca ataagcccaa tggatatcaa gctttangga gaaaatggat ctggcctggc 240 ttggtgcaag acaagaacag gttaccttct gctgaaaggg atgtgaggtt ttcaaatttg 300 gttttcatgt catagtttcc aaataaaatg aaccgctcca ccaaaaaccg acagtctagt 360 tngctaccta tcttccaggg gtttcatcat acagccattt ataangcaca ntctttggaa 420 ccgctctata ggtttcaaaa aagtgttttg aaggtcttgg aggggtgcat gttaactact 480 ttctcatcct cctgnttttc ctatttggca tcaatatatc tctcggcttc aagngggagt 540 caatgaaccg taagtggggc tatttnaagn gggngctgng gcctcccaaa aaanggnttt 600 taccaggggg aaaaantnnt ttttngtcca nanggggtaa gtcttnggga aanaaatttt 660 gccgnggaat catttggaaa aanaannagc ntttgggggn attgggccaa aaantncccc 720 ncccttgggt ttccagnggc ccttccgggn gtnttttnaa anntgncaag ggtcttngcg 780 naccttnttt acaaggtttt gccggatacc ttatactngn caaggtggtt tcggg 835 <210> SEQ ID NO 23 <211> LENGTH: 761 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(761) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 23 ggccgcagtg tgctggaatt cggcttagcg gccgcccggg caggtactta tgggccaggg 60 caatggcgac agcagacacc agcttctgcc aggcagcctg cacttcaggg gtgaactcct 120 tgccaaagtg agtagccaga ataatcacca tcacgttacc caggagcttg aagttctcag 180 gatccacatg cagcttgtca cagtgcagct cactcagctt agcaaaggcg ggcttgaggt 240 tgtccatgtt tttaatagca tctccaaagg aagtcagcac cttcttgcca tgggccttga 300 ccttggggtt gcccaggatg gcagagggag acgacaggtt tccaaagctg tcaaaaaaat 360 ctctgggtcc aggggtaaac aacgaggagt ctacccaagg cttaccttca gctcttncac 420 attnatcttg cttcacagct agtgacngca gncttctctt aacagtaaaa tgcaccattg 480 atgcnngncc tgaancttgg ttgtgatttg aantttnttn ggaagcaaan tttccccggt 540 tncctgggcg ggacncctta agccgnantt tgnanattcc ataancttgg nggccggtng 600 acatgctttt aaagggccan ttcncctntt gggngnggtn taaaattacn ggccggggtt 660 tanactngng acngggaaac ctggnttnca anttattgct tggaaaaatc ccttttccag 720 tngggtanan aaaaggcccn ccntcgcttc aanngtggcn g 761 <210> SEQ ID NO 24 <211> LENGTH: 784 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(784) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 24 ctagtaacgg ccgccagtgt gctggaattc ggcttagcgt ggtcgcggcc cgaggtactg 60 tatcacttag tatacccttt aaggtagcac ttatccagtc caaaactcca gtgacaaaat 120 tcctagttta tcaagataaa cacagtnaca ctggattaaa ggaaaaacat tgctatggta 180 tagactgtgg ttggcttcta tccagtaacc ttgggaatga agacatcttt gtaaacaagt 240 cctgctgttt ctttaacagc taacatagga aataattaaa tgtattcttt agtgccaatt 300 gtaagtttta aaatcaagaa tggcagtgta acttgtgaat tggctagggc aatcaatcac 360 aagcactact ttctgtaaaa ctttagtagt tcaagtgtta ccagttntac ccantctttg 420 gtgaattcca acttgtttgc ttaagttatc ttctttagng gtttcctggn gggttttcaa 480 tgctcttcgg nggngtcata atgccctccn tngccacttg gggacaactg gncccccttt 540 tttgaggggn taatngaatt tacttccncc cacaanaccc aaanagttng natnggnctg 600 ggantntang gcngcttcca aaangaatct ttttaaaaat nttnangttn ntggnttaga 660 nccgcccggg gggcgcttaa anccattttt gantttntna aactggggcg tttggctttt 720 ttnagggcca antncccntg ngggggttnn antaatnggn gggnttaaaa gtngnnngga 780 annt 784 <210> SEQ ID NO 25 <211> LENGTH: 782 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(782) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 25 ctagtaacgg ccgcagtgtg ctggaattcg gctttcgagc ggccgcccgg gcaggtacta 60 taacaggagt tctaatagag atgagggcag agtgcccaag gatgagtagc aactgaaagc 120 ttatatgatc cactgagagt agttaaaaaa aaaaaaaaat agtacccaag tctcacctct 180 tcttcactgc cggaaaagat cataagattt aaacagtggg atgcagacaa ttttgacccc 240 ttccagactc tgggngggct taacnggaaa atttggnngt tggcttntaa gccccnnngg 300 gnnctttntn gnnttattct tccnnnncna atttttngna nntttggnnn aaaccagggg 360 gccctttttn ttntgaggaa aaaaggngat tggaaaagaa accanatttt ngnggggnng 420 gnggccaaan anaaccancc ngcttttccc gggagnanct cagggggacg gttcctttnn 480 tgggaaagaa actttttnaa cagtnaaagc ccntnggagg tttnttggng gcttttgggt 540 ngnccttggc cgggnnccct tnagcccgan ttttgtgnat tttcnttaan actngggggc 600 nnttttggcn tttttttnna ggggccaatt cccctttttg ggggggnttt nnantactng 660 ggcgttttcn cccgnngntn nggaaaaccc gggttnccca ttttttngnt ggggaantnc 720 cttttccngt tggttttnna aagggccccc nntncttncc aangtngccc ccgnagggaa 780 gg 782 <210> SEQ ID NO 26 <211> LENGTH: 785 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(785) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 26 cctagtaacg gccgccagtg tgctggaatt cggcttagcg tggtcgcggc cgaggtactg 60 tatcacttag tatacccttt aaggtagcac ttatccagtc caaaactcca gtgacaaaat 120 tcctagttta tcaagataaa cacagtaaca ctggattaaa ggaaaaacat tgctatggta 180 tagactgtgg ttggcttcta tccagtaacc ttgggaatga agacatcttt gtaaacaagt 240 cctgctgttt ctttaacagc taacatagga aataattaaa tgtattcttt agtgccaatt 300 gtaagtttta aaatcagaat ggcagtgtaa cttgtgaatt ggctagggca atcaatcaca 360 gcactacttt ctgtaaaact ttagtagttc agtgatacca gttctaccca atcttggtga 420 attccaactt gtttgcttag ttatcttctt tagtggtttc ctggggggtt tttcaaggct 480 cttcggnggg gtcataatgc ctccnttgga anctgntgac aactgncccc ttttttgaag 540 gggttattgn aattaacttc ctccacatac caaaaagttg gtatgngtcg gganatatgn 600 ctngcttcca taggaatctt tttaaaaatc tttaacttca ctgggntaag anccggcccg 660 ggcggccgtt gaagcccaat tntgnaatnt tcatanactg gnggccgttg ggcatgcttt 720 agagggccaa ttcncctttg gggnngttta naatacggcc ggngtttaca cggnggacng 780 ggaat 785 <210> SEQ ID NO 27 <211> LENGTH: 777 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(777) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 27 cgagctcgga tccactagta acggccgcca gtgtgctgga attcggctta gcgtggtcgc 60 ggccgaggta cctgacgcgg ggcaagattc tgctgtgcac aggtgccatc atggaagaac 120 aggcagcaga actccttgga gtgaagatgt gcacgtttgt tccaagacac acccggaact 180 tggcaaatga gtttcgctgt tatgtgaatt atgattctgg gctggactgt gggatctgat 240 tacagacggt gacataacac aggaaggaac cctgtcacat tcctcttttt gtattttcgt 300 agtagattta aaagttataa tctcttcccc tccccccaaa ctggagctgt ccctggcctg 360 gttttcaaaa taaagtgtgc gatctccana naaaaaaana taaanantaa aaanggtncc 420 tgcccgggcg gncgctcgaa agccgaattc tgcagatatt catncacttg gcgggcgntt 480 cgacatcatt ttaangggcc aattcgcctn tagggggcgg attacaaatt aatggccgcg 540 gtttccaacg tngggactgg gaaaaccctg gggttnccaa ctttantcgc cttgagnaaa 600 tccccntttg cagttggngt aatagcnaaa ggccccnccg atcgccnttc aacantgcnc 660 acttgatggg naatggcccc ccttacgggc cttaaacccg ggggtnnngg ttnccccagg 720 tgccgttcan ttgcanggcc taggcccgtc ttggttttcc ttnttttgcc gtngngg 777 <210> SEQ ID NO 28 <211> LENGTH: 787 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(787) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 28 ggccgccagt gtgctggaat tcggctttcg agcggccgcc cgggcaggta cgcggggaga 60 gcagagtacg agtctgaggc ggagggagta atggcaggac aagcgtttag aaagtttctt 120 ccactctttg accgagtatt ggttgaaagg agtgctgctg aaactgtaac caaaggaggc 180 attatgcttc cagaaaaatc tcaaggaaaa gtattgcaag caacagtagt cgctgttgga 240 tcgggttcta aaggaaaggg tggagagatt caaccagtta gccgtgaaag ttggagataa 300 agttcttctc ccagaatatg gaggcaccaa agtagttcta gatgacaagg attatttcct 360 atttagagat ggtgacattc ttggaaagta ccgtagactg aaataagtca ctattgaaat 420 ggcatcaaca tgatgctgcc attccactga agttctgaaa tctttccgca tgtaaataat 480 ttccatattt cttctttttt aataaactaa tggttacnta attgccntcc canngntctc 540 caaaattnnt ttccttggcc cggatttaaa cnccttccaa ataaaaattt gggaaannaa 600 aaaanntnnt ntnnantntn gggtcccttg gncgggcccc nctaagccga attntggaan 660 ttccttacac tggnggccgt ttgncttgct tttgngggcc catcnccttt agggngnngt 720 ttacaatnac tggccgggtt tcacgtnggg ctggaaaccc ngggtnccaa cttattgctt 780 ggaannt 787 <210> SEQ ID NO 29 <211> LENGTH: 801 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(801) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 29 tnntnnnact nggtccctag taacggccgc cagtgtgctg gaattcggct ttcgagcggc 60 cgcccgggca ggtacatttg ggaacacaga gaaatcatct taggtatata aaagaaattc 120 aattatgaaa agccttgaaa acgaacctga ggagtttgga ctaaaagcaa aaagaaacca 180 ttataagaat ttatgaagta gagtgacatc atgaaagttg tcttttagga aaagtcacct 240 ggcaacagta tgaaaggtga attaggagag aatgagagga tgtagattag tcaagagact 300 atcagttatt ggatgtgaat taaagagatg acctttgtaa tagggaagag tggagagact 360 gaggcaattt cagaaaacta ggtagagcca ttttctcatt aagagccttt ggctgcaagt 420 aacagaaatg agattaaaca acaagaaaaa atattgagtc ccactgctgg ttatccaaat 480 gtagtgccct ttcangggca ngctttcctc cagttttttt tccacttcat tttttccagg 540 attnaattgg cctcaagggc tcntttnttt tgcnaggcnt ttttttccag ggtggcttga 600 accctaggga ctttanttcc atcacntccn cccatgaaca aatccatgan tggttgtcct 660 tggccgggac cnccttaacc gaattttgga atttccttac acttggggcc gtngncatct 720 tttaagggcc attcgcctta ggngngttta caataantgg ccgggtttan acnngggcng 780 gaaacccngn tnccaattnt c 801 <210> SEQ ID NO 30 <211> LENGTH: 802 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(802) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 30 tcntactcgn tccctagtaa cggccgccag tgtgctggaa ttcggcttag cgtggtcgcg 60 gccgaggtac ccaatgaagg atccgatgaa tggctggcca gttactcaaa gtaatatgtt 120 tatgagttaa atgggattgc ataacggcac cacttttcct ttgtcactgt ggtggataaa 180 tgacaaagta gattccaatc tcctgtatag aaaggtggtt acccaatagc ctcactggtg 240 gcttgctagc agagcctcaa gttgcacctc tgtggctttc tgtaaattcg agtcctacag 300 ccacttcgag aacgctgcaa tccccaaggc ccacttggtc catgctgaag aagcggctgt 360 gaccccaatc ctgcctctct tttgctcttc agtattactt actggaggaa tatgtnatat 420 tctaggtcaa gtctangaga ggctcatcct aaaaaaaaaa ttgcaaaagt cttttctnna 480 ttaaaacaaa aaaaagcctc aagtncctgn ccnggccggc cgctntnanc cgattnttgc 540 ananttcatt taanattggg ggccggttgn gcattgcttt taaaggggcc cattcnccct 600 tanggnggcg gnttacaatt caactggccg nngtttacaa cgtcggggac tgggnaaacc 660 ctngnnttnc caacttattn gcttgnaggn nattcccctt tcgccagttg gngtnatacg 720 aaaaggcccc nccgatcgnc ttncaaantt gccacctnat tggnnatggc cccccttatn 780 gncntancgc gggggnggng nn 802 <210> SEQ ID NO 31 <211> LENGTH: 751 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(751) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 31 ctagtaacgg ccgccagtgt gctggaattc ggcttagcgt ggtcgcggcc gaggtaccac 60 tgtgattttg ctaaactttc caaacttacg ctatcatgaa gttttttcca tttaatttga 120 gtattgctat aaccagtttt gattcaaaca aaatacaaac caagactgta tcagtcccac 180 agagagaaaa gaatactgaa tgacttatag ggttaatgaa atgttctaca tagccattta 240 ggccagtttc tgaaatggca ctacagctaa cttgcttaga gttttacctg ggctgctgga 300 ggaaagctat ggcacgaaag ccgatgtctt tcctataaat tgctccctca aactttatag 360 cagctagtcc tttcttggct tcctcaaggg ctgatatgag attttcccgg atggctgtga 420 ctgcaagaac tctaccccca tgagttacta ctttgccatt tttgagggca gtgcctgcat 480 ggacacctcc agcctagagc ttgagcctaa ggaacccttg tntttttccc cccttggggn 540 ancntcaggn taacctttat tggccatgac accagttang ggngggnngg ttttntacca 600 accngcagan tgggcanaca gccatttaag gggncngatc acttataaga anctttanaa 660 gggggaggat actggccttg gacacaaacg gaataactta aacttnggca tntggcacat 720 ntcactaaaa accgnttggg nccgccgggc c 751 <210> SEQ ID NO 32 <211> LENGTH: 787 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(787) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 32 tnnntcctnc tcggtcccta gtaacggccg ccagtgtgct ggaattcggc ttagcgtggt 60 cgcggccgag gtactctgtt gtatagctaa tacaagttag gatgcttttg gccagaggta 120 acagtgtcca aatataattg gcctaagtaa cctaggaaat tgtttgacat aacacagggt 180 tcaggggtgt cattaaagac acactttttt tgccttgacc tcagttggtt tgttttgcct 240 taggctattc cacctctcga tcacaagagc tgctgctata acttccagtt ttacatcttt 300 gtaaaattgt atctcaaagg cagaaaaggc catttcgtct ctcatttgtt ttatccatga 360 ggaagatttt taacaaaagc ctccaganga tttcccctca gtttccattg acttagatca 420 ggttacagag aaaggcaatg tctgacattt tttggtctct gttagaagca gactctgttg 480 aaaagaaaga agctaagcta ggtgtgaaga atgggatttg gaagcccnct ngctttccat 540 tagaaanggt tncntaatta cccccttttt ttggggtagg aatttggatt tttggangtt 600 ttnncnccaa ccannggcaa agggattgcn ttgncctncc ggggggncgt tnggntgctt 660 tttanngggc caattcncct ntangggggt ttacaataac tggccgnggt ttacaacgtg 720 ggctnggaaa ccctggngtt nccaattatt gcttnngaan ccctttggag gtggttanac 780 naaggcc 787 <210> SEQ ID NO 33 <211> LENGTH: 773 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(773) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 33 ctagtaacgg ccgcagtgtg ctggaattcg gcttagcgtg gtcgcggccc gaggtactct 60 ggagtcacca gcctctggta gattatcaag catctcttcc tcatcagcct tttgtttctg 120 tcttgcatgc ttctctgtcc actgtctggc attcttgagg aaggctggct tattatattt 180 aaattctgag gatatgtcag ccatgagcgg gtcatcaggg ttgggttctg acatgagcag 240 ctgaatagag gtcaacacag ttgcgatgtt gagggatggt ctccaagcac cttttggtgg 300 caatttgaga acatccagac aaatccttcc agcagaatca atgtttggat gataaattgg 360 agtgagaaat cggatctgag gaggttcaaa tgggtacctg cccgggcggc cgctcgaaag 420 ccgaattctg cagatatcca tcacactggc ggccgctcga gcatgcatnt anaggggcca 480 attcgcctat agtggagtcg tattacaatt cacttggccg ncggtttaca aacgtngngg 540 attgggaaaa ccntgggttn cccaacttat tcgcttggan gaaatcccct ttgccagtgg 600 ngttttagcn aaaaggccgc nccgatcgcc ttccaanngt tgcncacctg aatggnaaat 660 ggcccccccg tacggccatt taancgcggg ggtntgnngt tncnccaagg tgacnntcat 720 tgccangncc taggccgtct ttgtttttcn tctttttgca attncngntt ccc 773 <210> SEQ ID NO 34 <211> LENGTH: 776 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(776) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 34 ctagtaacgg ccgccagtgt gctggaattc ggcttagcgt ggtcgcggcc gaggtacaca 60 tttgctgatg gcttctcaaa acctgagccg agaatagggt ctgatagccc agccaagttt 120 aaaagcagac acacacgaat gtagtatcgt tgtgcctgaa atgaccattc tgggttgttt 180 agaatccaga atcatcaaaa gccatgtggt atgaggaagt aataaatatc ctcttgaatc 240 ttcttaccct attttgcaca aatggatggc tgcatgaaca gctcttgtaa attgctctga 300 gtccacacca atagaaacct gcactcattc tatagctaca gagggtttgt tggcttaagg 360 ggactttatc atctcagcat taatttccct tttaaagcta ttctcaaggn tggactgtct 420 cagagataaa caaagaggaa tccttttggc ttagaagcca actggcttac tcagactttc 480 ttccctttct acctcnattt ccacacttcc aatattatct ttttggacta ggaaatcaaa 540 tnttttcntg gactaanggg gcaggttatt ttttttccaa ccctgtccct ggnggccaat 600 gggaagaaaa tncccggccc tttgggaann gnatttganc ngccttttgt tttaaccntt 660 angcccaanc tccanggcna nttngaaggc cntaagggtt nactgcngga agccactccc 720 ntgnaaagtg ccatcntnta catgggntca acgggacttt caggtttntt tcttgg 776 <210> SEQ ID NO 35 <211> LENGTH: 772 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(772) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 35 ctagtaacgg ccgccagtgt gctggaattc ggcttagcgt ggtcgcggcc gaggtaccaa 60 cagtgataat aaattctcct tctggatccc agactaggtc ttggacacca tcaaagtgtc 120 ctgaaatgac aatctctgga gtccactctc tctgttctag ccaaactcct gactcttcat 180 ctggagccca gagaatcatg gttttatcca tggaagcaga taataatctc attggctgct 240 gtaggacacc atctttgtaa aacacaggtt gccagtgaac tgcatttacc cagttttcat 300 gaccggctag cactgtctcc agagtaacag caaatgctat tttaacactt tcattttcta 360 tggtaaaagt attttctttc agtcttatgt tatcgtcatc ctgagtttct aaagatgttg 420 actttatata cagcttccat attcttatca ggcaatcttg tgaacagctt gctaggaaaa 480 agatctctac aaangntggc catttcactc ctttaatcca atccctatgt tcacagagag 540 gnaagacctt ntggaacctg tnaatttngt ggngcaaant ttgaatttgn aanattattg 600 ccnatngcta annttgtacc tgcccggngg ccgttcnaaa gccgaatttt ggaaattcct 660 taanactggg ggcgtttgag nttcattaan ggccaatttg cctnaggngg ggttcaatta 720 anggcgngtt taaacgnggn nnggaaacct ggggtnccan ataatgnntg aa 772 <210> SEQ ID NO 36 <211> LENGTH: 774 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(774) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 36 ctagtaacgg ccgccagtgt gctggaattc ggcttagcgt ggtcgcggcc gaggtacatg 60 acctaatttt tacatcatag taaaacaggc cctatggaga gaggacatgg gtttctctgc 120 tgaacagcca ttatttatac tcgttccaag gcttctaaca tgatgatact atttcctcgt 180 attaccacca ttccaatatt gttctgttgt ccactagtcg ccatctccac acattcatct 240 atcacaaggt tcataaaggg atcaaatccc cgcaatattc cttggacatg tctgccacca 300 tttaatttca atgataactt cttgtccata aattttttca actcgggagg gtgagctttg 360 ctcatggtgt atactccgcg ggctcacaga tgccttggaa cgcaacgcac gggtttcctn 420 acgcttccgc tcccgcgtac ctgccgggcg ggcgctcgaa agcccgaatt tgcagatatt 480 cattacactg gcgggcgttc gagctgcatt tttanggccc anttcnccct ttnngggngt 540 ggnnttacaa ttaactngcc ggnnttttaa acgtcgggac tgggaaaacc ctggngtncc 600 caacttnatg gcttggagcn atnccccttt ngncagttgg ggtaataacn aaaaggcccg 660 accgntcgcc cttccaaang ttgccaacct aatggnaatg gacccccctg tacgggcatt 720 nacgcggggg gggnnnttcn ccagggnacn ntaaattgca gngcctagnc gttt 774 <210> SEQ ID NO 37 <211> LENGTH: 818 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(818) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 37 ttnnnnnnnn ncnnanctcg gatccctagt aacggccgcc agtgtgctgg aattcggctt 60 agcgtggtcg cggccgaggt acttaaatca gaaggatcgt aggcctgata agcaggtcaa 120 cctgaagcta ccaggcagct ctggaggctt ccgtggccat agctaacagt gcacaggagg 180 gcccctggcc caggatgagc cctcagaacc ttttagagag agtgaaattc agggtctact 240 gggtgtccaa gctgcagagt ggagccgtga gaggtcagct gccatgtgat agaaagagct 300 gacataagag aaaagacccc cacacagtga aaagctggaa gagaaacaaa actcacaacc 360 tgacagcaga gttcctggtt ccaactgttg agacctgtct ctacctccaa tggtcacaag 420 tatatagtta cccaggcctg gaaatctccc tcttttccta attagtttaa ctnggtgttc 480 ctgntngttg gaaaacagca acctgnattt tttaagacac ncttgngcaa agttnaaaag 540 gnggtgggga ccggtcctgn aaagganatg atgggnaagg caaaacttgg ctggcncnan 600 tgtntttttt ggccaaaaag gnaagggggg gccctttttt tntngcaaaa accctttttt 660 tttggaaata acttgggcnt ctttctngna cctgcccggg gggcggtnaa gccnattttg 720 gaattcnnaa acttgggggc gtttnctncn tttaagggcc attcccnttn nggggggttt 780 naantaatgg gcgcggttaa ncggggangg gaaanccg 818 <210> SEQ ID NO 38 <211> LENGTH: 815 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(815) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 38 agnnagnnnn nagnagagng gnnnnnnntt nnnnnnnnnn ngnnccgagc tcggatccct 60 agtaacggcc gccagtgtgc tggaattcgg cttagcgtgg tcgcggccga ggtacaatat 120 atttactagg ggaaaaactg tctatagtag caccatcttc ttcctttgaa tgggaaaagt 180 ttgaccaaga agcaacataa agtattagca gcaaaatact gttgaaccag ctatcatccc 240 caagactccc actataaaca tgttagcaac agtgatacac actgccttac agcaattttt 300 ggctgtaaaa atctagccaa ttcagttttt tgatatttgg tttttaatag tcttgttcaa 360 gtaagaaact agctgctagt tggactgagc ctgttctgaa aagacatgga agattcatta 420 gaggcacaca attgcttaat gtgagactta ctgaaaaaca aaagtcacat taccccctag 480 cttaaggctt catttcctaa aaagctgacg tgatttattt ttagaaccac ctgtcaagtc 540 aagtcttgga anggggattc tgatttgaag tatttctaac ctgatgttag acccttaaaa 600 actcaagacc atcttgagtn ttaaccaccc ttaattaatc attttttata gaagcccaaa 660 acancccaat tttttttcct ttttttgaat aaacaaaagc cctttgattc catttgccga 720 cnctttttaa aaaattccct taaaattcnc ttggaaantt ttnatnagng gacaccgnnt 780 gtnttccttg anggggnann tttgcttatt cnttt 815 <210> SEQ ID NO 39 <211> LENGTH: 816 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(816) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 39 agnnnntnnn nnnnnnnntn ntnnnnnnng ntgntccgag ctcggatccc tagtaacggc 60 cgccagtgtg ctggaattcg gcttagcgtg gtcgcggccg aggtaccttt taaataagta 120 taagggatgg caaagttttt ccctttaaaa atactcactt tatgcttata aataggttaa 180 tgggctgata aaaggttttg tcaaacattg caagtattcg gtgctatata taaaggagga 240 aaaactagtt ttactttcag aatgatttaa acaagatttt taaaaacaag atacatgcaa 300 gcgaacagca gggttagtga taggctgcaa ttgtgtcgaa catcagattt tttgttaaga 360 ggagcaaatg actcaatctg atttagatgg aagtttctac tgtatagaaa tcaccattaa 420 tcaccaacat taataattct gatccattta aaatgaattc tggctcaagg agaatttgta 480 actttagtag gtacctgccc gggcggtcgt cgaaagccga attctgcaga tatccatcac 540 actggcgggc gctcgagcat gcattntaga gggcccaatt cccctatagt gagtcgtatt 600 acaattcact gggccgtcgt ttacaaccgt cgtgactngg gaaaaccctt ggggtnccca 660 aacttaatng ctttgnagga naatcccctt tttncantng ggtaanaccn aaaaggccnc 720 ncnatccccc ttnccaacat tggncaacct gatngngant ggacccccct gngcggncca 780 taaaccgggg ggngnggngg taccccacgt gacnnn 816 <210> SEQ ID NO 40 <211> LENGTH: 821 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(821) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 40 nnnnnagnnn nnnnnnnnnn nnttntnnnn ntnngttngn accgnctngt ccctantaac 60 ggccgccagt gtgctggaat tcggctttcg agcggccgcc cgggcaggta cgcgggacgg 120 gaagtgacga gagccgggtg gacccagggt ggggaactac ctcttcctct ccacgcggtt 180 gagaagaccg gtcggcctgg gcaacctgcg ctgaagatgc cgggaaaact ccgtanngac 240 gctggtttgg aatnagacac cgnantgaaa aaaggggaga cactgcgaaa gcaaaccgag 300 gagaaagaga aaanagagaa gccanaatct gatnngactg nagagatagc agaagaggaa 360 gaaactgttt tccccaaagc taaacaagtt aaaaagaaag cagagccttc tgaagntgac 420 atgaattctc ctaaatccaa aaaggtaaaa aagaaagagg agccatctca aaatgacatt 480 tctcctaaaa ccaaaagttt gagaaagaaa aaggagccca ttgaaaagaa agtggtttct 540 tntaaaacca aaaaagtgac aaaaaatgan gagccttctg aggaagaaat agatgcttcc 600 taagcccacg atgnttngct tncttacccc anaaccaant nggtcccttg gccgggaccc 660 ccttagccga attntggana tttccatnan actgnnggcg gttcgncttg nntttaaggg 720 gcccattccc cctttagngg ggnngtttac aattactngc cggcgnttnn acgtngtgnc 780 gggaaacccg gggtacccac ttatngcttg agacatccct t 821 <210> SEQ ID NO 41 <211> LENGTH: 825 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(825) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 41 tagntannnn nnnnnnnnnn nttnnncnnt nnnttnnacc ganctcggat ccctagtaac 60 ggccgccagt gtgctggaat tcggcttagc gtggtcgcgg ccgaggtact gcccacgaag 120 ttcttccaag gctcccccac tgcatggcag gcaagcattt tcaatggccc ctgctgacaa 180 tgaccttggt ggtgttttac aaagtgtttg caattcttcc aatttattct tcatgtcgtt 240 gttttcttct attaattctt caacaacttt attattctct tctccaattt tttccactac 300 agctttgtgc ttcctttcta aatgctgaag atgcctacag catttctcca gttttccttt 360 cagatcttga cattcctgct ttgccttttc aagttcttgg aagcagtgtc cacagcataa 420 atccttaatt tcaaggacct ttttcttatc agcttctgct tctgttgctt gtaaggccaa 480 gggctgagca tggtgtccag cagcaggtcc agggtctcct tggccagtgc cctggctggc 540 agaatcctta gagagctcgg ccatatttct ctttttccat tctgggtcaa cggttttcta 600 caagcaaang aagtgtatct tggaaatgct ttctttatgc agccctttag tttttcaaaa 660 anattgcaca agaccatcca tttttgaaaa acaaggcgac attgttttcc aaaaagcttg 720 nttgtcctaa aancnactga nngctctttt gggttcacta aaaaaaaccc aagncctgnc 780 cgggngccgt tcgaaagcca attttcaaaa tcatcnnccg gggcg 825 <210> SEQ ID NO 42 <211> LENGTH: 799 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(799) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 42 nagnntnnnn nnnnntnnnn nttnnnnncc ngttngnacc ggctcggatc cactagtaac 60 ggccgccagt gtgctggaat tcggcttagc gtggtcgcgg ccgaggtacg tctccactct 120 gacagatcag gtgaccctcc tcatcatcct ctacactcct ggttcttttc cttcggtgac 180 tcttctggaa acgtcaagtg ggcggcacca agatcatcca gccaatcaat atacccgagt 240 gaattcaggg cagaatacga aattcattca gcggggagat attcaggcat tcagatacac 300 gccaggccac aaacggttgg caggagcaat ttcaaattca gtccccagaa attcacaggg 360 cacatagttt atgttaacag gagaaaaaca tggcaaggaa cagattttca gataagatac 420 tcaaagtggc aaggcaacaa aacataatac aattgttttt cttaaaaaaa aaatgcttag 480 ttgtagcatt cactgaaaca taatttttta gtttctagtg ttctaattta atgttgcaaa 540 atcgtatgat gtaatattta cttgtcaaag taggcnggng gccaaattaa agattcctac 600 ctatctaaga aaacaaatnt tttaccgtaa ataaattaaa gngctaattt tggggaaaaa 660 gattngcntc caaaataccc tacgggattt taangcatct gactgnctcc tntatatnta 720 nccctacagt caaattttnt ggttgctagn aaaaaggtta aaanatgntt gtanacaaan 780 agcttcctat ctaatttnc 799 <210> SEQ ID NO 43 <211> LENGTH: 806 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(806) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 43 nagnnagtnn nnnnttnnnn nttntnnnnn nttngtnccn gctcggatcc ctagtaacgg 60 ccgccagtgt gctggaattc ggctttcgag cggccgcccg ggcaggtacc ccaacctcca 120 gcatatcaag gggtaacagt tccaacacca ggtcaggatc aagctcagca tccaatgtca 180 cccagcgtta tagctcaacc tttggacctg ggacttacca tcactccaga acccactaca 240 gaggttgaac attctacacc cctgaagaag attcctccca agcaccctaa agtgacactt 300 cacatccaga ccaggttcag actctccatt cgaacctgac tcaagtcaca gttcaacctt 360 tggatctgga acttacctta actccagaat ccactatgga ggttgaacct tttccaacca 420 tgcagaagac cccaactcag cctccagagc tacgtaagga ggttgtagct caacctcctg 480 tgtattatga gacgtncatg ccaacacgag gccaggatca agctcagcat ccaacatcac 540 ccagagtcac agttcaacct ttggatctgg ggcttaccat cacttccaga atccattaca 600 aaaggttnac ccggntacag ccttgttgat tcaggttctt ctcaaaggac cttgngnggg 660 nncttccccc nccngacaag gntaagggtc aaaatttnaa acctnattta agntacagtt 720 aaactttgga cnggggcttc cttacttttg aacntctttg tgttaaccgt tcacccgggg 780 gaactaactn tttcanctgg ntgcnn 806 <210> SEQ ID NO 44 <211> LENGTH: 795 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(795) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 44 agnangnnnt nnntnnnnnn ntnnnnnnnn nntnnntccn nctcggatcc actagtaacg 60 gccgccagtg tgctggaatt cggctttcga gcggccgccc gggcaggtac aaaattaaca 120 tcaaaagacc tttgtaaaat gatgcctttt gatgatcttg tgacaagggt caggagatgc 180 ggagaaggga aagggaattg gtctggcagg ctgaggaatg tgctccacat gcaagtgaaa 240 aagcgaggat ctgctaagct cccggaaact ctgcctcttg attagtcatc ctgggacatt 300 acccaacctt ccttgtgtct gttgctgctg agtttcataa tcccattcaa tctacactat 360 aatcccattc aattttacaa tccattataa ttctgagtat gaaacagata tttggggagt 420 gcgaaaagga gaagggaaaa agcaagcaaa gaaagtgtct tcagaccaag catgcagtca 480 ttgagaggaa gaatctggag ttcgtcaggt tgaccatatt cataccctgc caaccaagct 540 caaaagaatc ttatctctat tggtttncag agaattgtct gtgagagaca acgttgaagc 600 tctgctgatt aatgnttggn gaacaaccca aatttttttc ccttngncng gnncncnctt 660 agcngatttt ganatttcat nncctggcgg ncgttgacat tcatttaang ggccaattcc 720 cttagngnnc gtntacaatt nctgccgntt tnaacgtcgg antggaaact tggtnccact 780 antgcttgac aatcc 795 <210> SEQ ID NO 45 <211> LENGTH: 814 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(814) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 45 agnnagnnnt nnnnnnnnnn nttntttncc nncttnttcc gagctcggat ccctagtaac 60 ggccgccagt gtgctggaat tcggctttcg agcggccgcc cgggcaggta ctgagccacg 120 atttgttctc tcaacacaca ggtgtttctt ttctctgact caggattctg agaagctgct 180 gcactgggga ccattctttt ctcaacctca acctgaaagt atctgccttc taattcatca 240 actggctggg tgctttctaa aatggtgtca ttgttttcaa tgagtttcca atcatcattc 300 tccagaaagg aaagaaatct gccatccttg cacagtgcat ccttgatggt ttctcctttg 360 aaagcataaa cacagagttt gcgccccttt ttgtgaagct tcccacattt aacaatcctt 420 cttttacact tcccaattcc aattgcatga atgtaaaatt tgacacattc agtcgatgct 480 ttgtcctgcc tgccaaatat gtggttatct tccttctgct tacttttact ttgggaaaat 540 gtnatgacca cctggccacc ttcanggaaa cactgagggg cattncaagg ttttgtacct 600 cggncgcgan cacnctnagc cgaattctgc aaantttcat cacaatggcg ggcgnttngg 660 cattgcntnt aaanggccca attcgccttt tntnantcnn attaacaatt nannggcgnc 720 gtttaacaac ntcnggantg ggaaaaccct gngntaccaa ctatntnctt ggananatnc 780 cctttntcca gtngnntaaa caaaagcccc nccg 814 <210> SEQ ID NO 46 <211> LENGTH: 815 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(815) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 46 agntnagnnn anntnnnntn nntnnnntnn ntttcttnnt tttntnnnna ntnanccttt 60 nacggncgcc agtgtgctgg aattcggctt tcgagcggcc gcccgggcag gtaccggggg 120 ttaggacttc aacttatatt ttgggggagg gaaccacaat taaatccatg ggagccagaa 180 aatgttttca tttgccattt aaggaaactt ctgtaaggaa aaaccccata tccctgttgc 240 aggtgtgatg gtgaagcagg tgtgagagct gagcaggcag gagttgcaca agtgattccc 300 ttgtctatta cttgagtggc cagacaccag gaggcagcaa gtagatttct ccaccgcctc 360 tgactantga agccctggga gttgcttaag cttatctact aaccaccttg acaggcttgt 420 aaaaattttg caacatcatt cttaaaaaag aaagaaaatc cagcagccag caaactgtcc 480 ataacagagc caaatgactc actgccagca ctgctctaca tgttttagga agtccttatc 540 atctttccgc caacacatcc aattattttt aaagcagctt ttttccagag ggatgcgttt 600 atttttttgn ngtaatggca ttctattcca aaagttaacc ccgntggttn ccaatnggag 660 nttctccaga ggcataatng gccagtgttt aaaaacagcn ctccaaaaaa aaanctnggn 720 gggggggaag ggctgnatag tctttgcaat ttccntgggg taaccccccn natggttnat 780 tcaacctcta tnggangtcc tngcnggacc cctat 815 <210> SEQ ID NO 47 <211> LENGTH: 809 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(809) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 47 aagnnnntgn nnnnnnnnnn nnnnttnttn ntnnnntnnn ncngagctcg natccactag 60 taacggccgc cagtgtgctg gaattcggct tagcgtggtc gcggccgagg tacctcatac 120 acacagttct gtgagatacc taggtttggg ggccaaattg gaatagataa aattctttgt 180 ccccgtgaag actgttcctg gccagatacc tttcctatgg gaagtccttc ataattcaat 240 tttccttcct ttatgaaact atatagtgga gaaccaggaa cagaattaaa gtcaccacac 300 ataacaatag ggcagaagct gccatctttc tggtgggcaa cactggaaat ctctgccagt 360 agcattgcca attgcgtcag cttaatatca cctcgccttg gattatacaa cagatgcgta 420 tttgctacgc agattgcagg gcaggcagca tatggaattt tgggctgtaa gagtaaaact 480 aatccaacat tgtctctgtc caacagagaa atatcagggc ggaagaattc cactgggttc 540 actgacaaga gtgaaaattt ggaatgtttg aagcaaatag cacaagccat caggttcctt 600 ctggccgcat tttatttcac agggntaacc cagtgattcc aacttggncn gantttggtc 660 attaangaac ttttngactt ttggnaacaa agacctgccg ggcggccgtt cgaagccgaa 720 ttntgcagat tncntanact gnggccgttg agcttcattt anaggcccaa tcgcctatag 780 gngcngatac aattactggc cgcggtnnt 809 <210> SEQ ID NO 48 <211> LENGTH: 833 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(833) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 48 nagnnnnnng nnnagntnnn tntnnnnnnt ttttttgtng nttntnccgg ctcggatcca 60 ctagtaacgg ccgccagtgt gctggaattc ggcttagcgt ggtcgcggcc gaggtacagg 120 gagaactcac agctccaaga gcttccctcc aaattatgat gaagttcctg taaataacta 180 gatttcctac agcctggtcc tctgcccatg ggaaggaggg gaaatggatg tgaaaagcaa 240 tgtggtctgc cctcctgtca ttcatagatc cagttctgag cacagctcgt gtaatctacc 300 agttcctcag ggtgaaacca caagccgatc tcnttctctg cactctccac agaatcactg 360 ccatgtataa tgttcctgcc aacttgtatg cagaagtctc cacggatggt cccaggcttt 420 ggagtctnca gggttggtct tccccgagca ttgacttggc ccgtctttac cacattcaag 480 cccttccaga ccatggncaa ctacccggcc cttgagtgca tggtntttca ccaaggccgg 540 caaagaaatg gaccggnncc ttcangncaa cgtaagtggt tcctttgaga agancnttcg 600 gaagcttggc atgaatttca naccaacaag gnggnatcct ttttggtnna aacgcttggt 660 anttttttcc caagaccccg gttggaccca tttggtttga tccaattaaa ggtccntgcc 720 cgggnggccg tttaaagcca attttggaan tttcttcacc tgggggcgtt gagntgcntt 780 aanggccaat tcnccttngg gggngtttan aattactggc ggggttaaac gcg 833 <210> SEQ ID NO 49 <211> LENGTH: 807 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(807) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 49 nnaggnaggt nnnnnnnnnn nntnntntnn nntnnnttnn tnnggcnngg atncactagt 60 aacggccgcc agtgtgctgg aattcggctt tcgagcggcc gcccgggcag gtacttatgg 120 gccagggcaa tggcgacagc agacaccagc ttctgccagg cagcctgcac ttcaggggtg 180 aactccttgc caaagtgagt agccagaata atcaccatca cgttacccag gagcttgaag 240 ttctcaggat ccacatgcag cttgtcacag tgcagctcac tcagcttagc aaaggcgggc 300 ttgaggttgt ccatgttttt aatagcatct ccaaaggaag tcagcacctt cttgccatgg 360 gccttgacct tggggttgcc caggatggca gagggagacg acaggtttcc aaagctgtca 420 aaaaaatctc tgggtccagg ggtaaacaac gaggagtcta cccaaggctt cacctccagc 480 ctcttcacat tcatcttgct ccacaggcta gtgacggcag ccttctcctc agcagtaaaa 540 tgcaccatga tgccaggcct gagagcttgc tngtgattgc agctgtgtcg gaagcagata 600 tgttcccgcg taccttnggc gcgaacacgc taagccgaat tntgngattt ccttaaantt 660 ggngggcggt tcgngcatgc atttaagggg nccaatcncc tntatgngtn ggttanaatt 720 natngccgnn tttaaacgnn ggnctgggaa acctgngttn ccacttantt cttganaatn 780 cccttttgcc ngtggganna caaaagg 807 <210> SEQ ID NO 50 <211> LENGTH: 827 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(827) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 50 ngnnanngnn annnnnntnn nnnnnnnttt ctgtnccatt ntggnnccga gctcggatcc 60 actngtaacg gccgccagtg tgctggaatt cggcttcgag cggccgcccg ggcaggtact 120 tttttttttt tttttttttt ttttttncgt tacatggttt tatatttatt ttattgaaat 180 tgaacatctn ttttacaaat gctaataaat gaatctattc attctctcat ttattcaacc 240 aatgttaatt gagcacttac tattacatgc cacttaacca gtttcactca gtttaatgaa 300 gcatttntat aaatccttga gcacagacgt ttctatgtat attgcaagct gtgtttgaca 360 attgagtagc aattgctgat gctggaaaaa aactaatgtt gcaaatattt nttgagtaat 420 tatatcagtt gttttggggt ttggcttagg atgtgggttc agaaagtctg aacctttcct 480 ggttctttta atcttcaaag aaaaatnggg ccctgctgct gagttganan aaaataatcc 540 tnggnccccc agcaaaccnn aattcncccc ccaacatngg gntaaaaaan ttgtagcccg 600 taccttggnn cgngaccccc taagccgaat tttgnagata ttcantaacc tngngggccg 660 tttgagcatn ctttaanggg cccantcncc ctnanngggg ggtgnttcan tanctngccg 720 gggtttcnaa cgnttgnntg gaaaaccccg gggttnccaa nttatatgnn tnggngnnan 780 ccctttgcan gtngggaata nnaaaggncc cncantggct ttncnnt 827 <210> SEQ ID NO 51 <211> LENGTH: 830 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(830) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 51 agtnnanagn agtnnnnatt ttnnnttntt tattntnntt tntnnngagc tcggaccact 60 anttacggcc gccagtgtgc tggaattcgg cttagcgtgg tcgcggccga ggtacaggga 120 gaactcacag ctccaagagc ttccctccaa attatgatga agttcctgta aataactaga 180 tttcctacag cctggtcctc tgcccatggg aaggagggga aatggatgtg aaaagcaatg 240 tggtctgccc tcctgtcatt catagatcca gttctgagca cagctcgtgt aatctaccag 300 ttcctcaggg tgaaaccaca agccgatctc cttctctgca ctctccacag aatcactgcc 360 atgtataatg ttcctgccaa cttgtatgca gaagtctcca cggatggtcc caggcttgga 420 gtctgcaggg ttggtctccc cgagcatgac tcggcccgtc tttaccacat tnangcccct 480 cccagaccat ggcaactacc ggccctgagt gcatgtattt naccaggccg gcaaagaatg 540 gacggtcctt caangtcnac gtagtgttcc tttgagaaga tctttggaan gcttgcattg 600 atttcagacc aacaaggggg gaatcctttt tgttaaaaac gcttggntaa ttttttccac 660 aaaaacccgt tggaccccan ttggtttggn tcgcattgaa agntccntgc ccggcnggnc 720 gntntaaagc cgaattttgc aaattnatca anctngnggg ccgttggnct tcnttaangg 780 cccaaatccc ttangggggg tttcanatac nngcnggttt aaactnngnn 830 <210> SEQ ID NO 52 <211> LENGTH: 826 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(826) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 52 tagagttnag gnnnnnantn nnntntntnt ttnannnttt ngtaccgact cggatcccta 60 gtaacggccg ccagtgtgct ggaattcggc tttcgagcgg ccgcccgggc aggtacaagt 120 gcaaaaaaaa ttccatcatt tgtaaagaga aataaaaagt gccagcctgc ttgttcttaa 180 aaatgcctcc cgacataatt gttcaaagac aaattagaca gatgcaacat taaaaaaaaa 240 aaacaaaacc ttcttagcat gccatgtcta ataaacacat atatacacaa aaactagaac 300 aaaatcatgt gaaaccgagt tatcaagctg gcattgatga actggtctgt aagttgttgg 360 gttacatcat aaaatgggat gtttcacatc tcgggcacag acgacttgga ggttgctctc 420 agagggcaga ctttttgtan aggaagtccg gcttgcttgg tgacctccct tccttctgct 480 tattgaatct tccctttcca aatntgtntt tctttgangc tccttggccc agggactcac 540 tgtttgcagt cttctaccgg attttttttn gggagcttna gagcttcntt ccaaaaagtg 600 aaggtncngt ntggagtcca gcccaaaaag tnanggcagt ttttactgna gttcggtccc 660 tnncttgggt tggaccggta ccttgccgng accccctang ccganttttg nanaattcnn 720 anctgggggc cgttngnctn cntttaaggg cccattcccc tttaggnggg nntanantta 780 nnggcggnnt tnnacgtgng antgggaaac ctgngtccca attaan 826 <210> SEQ ID NO 53 <211> LENGTH: 752 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(752) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 53 cctagtaacg gccgccagtg tgctggaatt cggcttagcg tggtcgcggc cgaggtactt 60 taaatttagt ggttgctgga gcacctaaaa gtcagattgt catgttggaa gcctctgcag 120 agaacatttt acagtaggac ttttgccatg ctatcaaagt gggagtgaaa tatacccaac 180 aaataattca gggcattcaa cagttggtaa aagaaactgg tgttaccaag aggacacctc 240 agaagttatt taccccttcg ccagagattg tgaaatatac tcataaactt gctatggaga 300 gactctatgc agtttttaca gattacgagc atgacaaagt ttccagagat gaagctgtta 360 acaaaataag attagatacg gaggaacaac taaaagaaaa atttccagaa gccgatccat 420 atgaaataat agaatccttc aatgttgttg caaaggaagt ttttagaagt attggtttta 480 atgaatacaa aaggtgccga tggcgggatt tggcttcact taggaatggt aagttgngan 540 gnagatatgt tttnaaancc ttcatggntc agctttnttt taaaagaggg caaacacagg 600 tgctttntnc ctgccnggcg gccgttcgaa agccgaattt tganantttc atacacttgn 660 ggccgtngng ctgcatttaa ngggccaatt gcntttaggg ntngnttcaa ttaatggcgg 720 ggttttcaac nnnnngctgg gaacccgngt tt 752 <210> SEQ ID NO 54 <211> LENGTH: 821 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(821) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 54 annnnnnann nannagnnnt ntnntttttn nnntnttgng gnccganctc ggatccacta 60 gtaacggccg ccagtgtgct ggaattcggc tttcgagcgg ccgcccgggc aggtacggag 120 ctgagaggaa gatctccagg cacagcgttt tgggtgcagc tgtcancgtt ggagttccac 180 anggcgtttc tctcanagtc aagctcaaca gggccagtca gacatacttc ttccctattc 240 acttgacgga ccagcttctg ccancgccat gttctatgcc acccgtgggg cctctagtag 300 gtctactttg ccatgcaccg tctgatcatc aaaccatacc tcaaggctca gaaagagaag 360 gaattgggag aagcagaggg aaagcgccgc cacccnatgt gctncagaag aagcaagagg 420 cggagtccgc ttgtcccggc tgatgcatga atctgtcccg aaggataatt gaggcanaag 480 agtccagaat ggacctcatc atcgtcaatg cctggtacct cnggccgcga ccaccgctaa 540 gcccgaattc tgcagatttc cattacactg ncngnccgnt cgagcatgca tttagagggg 600 cccaattcgc ctntanntga ggcgnattac aattcactng gcgggggttt acaacgtctg 660 gctggnaaaa ccctggnntt ncccaactna ttgccttgna naacattccc ntttgcnagt 720 tngggtaata ttanaaaggc cggaccgatn gcctttccaa naatgcccac ctgattggnn 780 atggcccccc ctttccggcc aatananccg gggntgngng n 821 <210> SEQ ID NO 55 <211> LENGTH: 733 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(733) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 55 cnnnnnnacn gncgncagtg tgctggaatt cggcttccta gcaagccaga ggaagggctt 60 ttcaaagttg tagttacttt tggcagaaat gtcgtagtac tgaagattct tctttcggtg 120 gaagacaatg gatttcgcct tcactttcct gtccttaata tccactttgt tgccacacaa 180 cacaatgggg atgttttcac acactcgtac cagatctcta tgccagttag gcacattctt 240 gtaagtaact ctcgatgtta catcaaacat tatgatggca cactgggctt ggatataata 300 gccatctctc agtccaccga atttctcctg gccggctgtg tcccatacat tgaacttaat 360 aggtcctctg ttggtgtgga acactagggg atgaacctca acacccaagg tggctacata 420 cttcttctca aattcaccag tcaaatgacg tttcacgaag gtcgtttttt cagtaccacc 480 atcaccaacc aatacaagtt tgactggcct ggggctntcc tgcgcaagcc atcgnggggt 540 tcctttcana agcgtttccg cgccccgtcc gatgaggctg gaagatgggg gncccgcgtc 600 ctcggccggg acccctaagc cgaatntgca atttcataca ctggcggcgg tcggcatgct 660 ttanagggcc aattcgcctn tgngagtgga tacaattant ggccgcgntt acacgcgnga 720 tngggaaacc cgg 733 <210> SEQ ID NO 56 <211> LENGTH: 746 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(746) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 56 cnnnnnnncn gncgcagtgt gctggaattc ggcttcgagc ggccgcccgg gcaggtactc 60 tattctctta tccaggactg gatcaaatga tttatggcat tgtgctgttt taatgttctc 120 atccacaggg tcgattccaa taactgaagc cccaagccgc cctagaggtt cagttaacag 180 cccaccacca cagccaacgt caagaatctt catccccaac aaaggttttc ctggctggtg 240 attaggaatt gttttcagaa gattgtccct aataaatggc accctcaggt cattcatgga 300 atgaagaggt gcatatactc cttgttcatc ccaccatttg tgagccaggg ccaagaaggt 360 ttttacctca ccgctgtcga cagtggtttg ggaagtacct cggccgcgac cacgctaagc 420 cgaattctgc agatatccat cacactggcg gnccgtcgag catgcatcta gagggcccaa 480 ttcgccctat agtgagtcgt attacaatta ctgggccgtc gttttacaac gtcgtgactg 540 ggnaaaccct gggggtaccc caacttnaat ggcttgcagc acaatcccct tttngcagct 600 ggcgtaataa cgaagaggcc ggacccgatc gcctttccaa agntgcncan ctgaatggng 660 aatggacgcc cccttancng ngcattancg cggnggtgng nggttcccnc angtgaccgt 720 acattgcaag gcctaaggcc gttntt 746 <210> SEQ ID NO 57 <211> LENGTH: 749 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(749) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 57 nnacngncgn cngtgtgctg gaattcggct ttcgagcggc cgcccgggca ggtacatata 60 catttgcaaa acttgagttt atatgcagct ttttaaagaa cagaacactt gcttgaagtg 120 agtttcccca aagtatctga atgcctgcca cactctcctc tcccccatta catggtattt 180 cctcacagtt cagattggca agtgcacttg gggtcactcc agacacatac cttgctcagg 240 agcctctgag tgcagctcct aaatatctgg ggcctacagc ctagacaacc cacttaagtg 300 ctaggtacct cggccgcgac cacgctaagc cgaattctgc agatatccat cacactggcg 360 gccgctcgag catgcatcta gagggcccaa ttcgccctat agtgagtcgt attacaattc 420 actggccgtc gttttacaac gtcgtgactg ggaaaaccct ggcgttaccc aacttaatcg 480 ccttgcaaga caatcccctt ttcgncagct gggggaataa cgnangaggc ccggaccgat 540 cgcccttccc aacaagttgc gcagcctgaa tggcgaatgg acncgcctgt agcggggcaa 600 ttaagcgccg nngggggggg nggttccccn caggnngacc ggttnacttt gcaagggcct 660 aacgcccgtt ctttggtttt ttccttcctt ttngcncgtt cgccggtttt cccgtaaggt 720 ttaaatgggg gctccttagg gtccgattn 749 <210> SEQ ID NO 58 <211> LENGTH: 735 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(735) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 58 tcctncangn ctgcccaggt nacctgacct gagtccctgn nntnncccgn tcagncncnc 60 angntgcaca tgtnacaacc gagcntactg gatcggtgaa agaaaataat aataatgagc 120 atctaagtgg ttgggtttta gagatcaatc aagaataatt taattttctt ttgtatttga 180 aatgtaaata gttttctttt cgattaaaaa aatttcctat aactgctaaa cagttaaaaa 240 ctttaaagta gtaaatgagt ttatagaaag catgtattct tgatttttgt gccttggtaa 300 agttgataac tatttatgaa tatttgacca aattattcca gcatcagaat aataagcaaa 360 ataactttgt tagtgttttg ttagactgtt tatgaaatat aacaagaaat actattttgt 420 gttggatggc ggttattttt aaacttaatt aatcctgtga aaaggcctct taccttatgg 480 tatataatta aacaaaatcn ggagaaatgt atcagnttgc tcaattatca agncttgctt 540 ttgccgctta tggnnctcta caccctgtaa gggttgttga aggaaagaga actaaggaag 600 gtntatttgc tagcgttttg taagtngctt ataagnaatg gggcctttca angcttctgn 660 ggatgattgc ttgtctggtt ctncgttaag gaaatgaact tgganaagga agcccttttg 720 aggtcaccgt cccnc 735 <210> SEQ ID NO 59 <211> LENGTH: 742 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(742) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 59 gnnnnnngtn tgctggaatt cggcttagcg tggtcgcggc cgaggtactc agggccggta 60 gttgccatgg tctgggaggg gctgaatgtg gtgaagacgg gccgagtcat gctcggggag 120 accaaccctg cagactccaa gcctgggacc atccgtggag acttctgcat acaagttggc 180 aggaacatta tacatggcag tgattctgtg gagagtgcag agaaggagat cggcttgtgg 240 tttcaccctg aggaactggt agattacacg agctgtgctc agaactggat ctatgaatga 300 caggagggca gaccacattg cttttcacat ccatttcccc tccttccatg ggcagaggac 360 caggctgtag gaaatctagt tatttacagg aacttcatca taatttggag ggaagctctt 420 ggagctgtga gtttctccct gtacctgccc gggccgggcg ctcgaaaccg aattctgcag 480 atattcatac actggccggg cgnttcgagc atgccnttta gagggcccaa ttcgcctata 540 gtgagtcgga nttacaatta acttggccgg cgttttacaa acgtcgggga ctggggaaaa 600 ccctggcgtt acccaactta aatcgcttgn agnacatccc ctttcgccag ctggngtaat 660 agcnaaaagg ccgaccgatc gnctttncaa caattgcnca ccngatggna atggacccct 720 gtacgggcat taacccgggg gg 742 <210> SEQ ID NO 60 <211> LENGTH: 736 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(736) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 60 gncgcagtgt gctggaattc ggctttcgag cggccgcccg ggcaggtaca aaaagtatct 60 atgacactag tattaaatta aaattaattt taaattttac cacaataaat gtatacatag 120 tataaggaaa actacagatg ctttcagatc accagtctag aacatattct gcaaagtggc 180 taattcacat tatatttttc ttttaatact gagttccata aaaatgcaag ttcttccatt 240 gtttgagttc tgaagtcagt attcattctt gcaaccaatg aacagtgttt tgagaaaaca 300 gttttctttg taaatattcc accaattcac gtcttgattt tagcatccca atctcatgat 360 aggggatctg aacaacttga taaccgagta actgtaggtg tctttgttta atagcttctt 420 tccccagtaa gtgtttgcta ttgggagcaa aacctttttg gaccatcaat acacaagggc 480 tatcctttta tnggatatct tcattagctg ngggatggca atacaaatcc ttcttcatta 540 atttaatttc aacatctatg gttaacaata gggtggcaac acttttggag caaaatataa 600 tcntgctcct aaaaggtagt cagcccaatc tttancatat ntttaaagtg ggaatccnan 660 gggtctccan ggaccacatg gggnaagaaa gacttccttg tnttaggaag gngtttggnc 720 ctttngaaaa ggnatt 736 <210> SEQ ID NO 61 <211> LENGTH: 776 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(776) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 61 tnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nntnnnnngn ncgncngngt 60 gctggaattc ggcttagcgt ggtcgcggcc gaggtacatg ttggaaaaat ccttctacca 120 gtttcagcat tatagagcaa ttccaggagt agtagagaag gtaaagaatt cagaagaaca 180 gtataataaa atagtaattc ccaatgaaga aagtgtggtt atctattata agattagaca 240 gcaacttgcc aaattgggta aagaaattga agaatatatt cacaaaccaa aatactgctt 300 accttttcta caaccaggtc gtttggtaaa ggtaaagaat gaaggagatg actttggctg 360 gggagtagtg gtgaatttct caaaaaagtc aaatgttaag cctaactctg gtgaactgga 420 tcctttgtat gtagtagaag tacattcttc ccattcatat gtattattta acctcagagc 480 atttgcgggt ttatacttat aactctgtat agaangatat tatatatnaa ccgtaacatt 540 aaanggaaga atatcaagtc tagtcatctc catagaactt tttcccccta atcttctaaa 600 tattggtaat caccgaaaat gtttagatgc tctcatggna attctgggtt acaatttntt 660 aaaacattct tggntntttt aaatacacca tanagggagc tttccatatg gttanaaaaa 720 ataaattgcc tttaatgccc aaaaaaaaaa aaaaaaaaaa agtcctgccg gcggcc 776 <210> SEQ ID NO 62 <211> LENGTH: 785 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(785) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 62 tnnnnnnnnt nnnnantnnt nnntnnnntn nnanacntnn tnacggccgc cagngtgctg 60 gaattcggct ttcgagcggc cgcccgggca ggtacatccc ccggctgcac agactcttca 120 gatctgttng cttgaacagg gacccatagt atgtggccag tgcagggtca tctctctgaa 180 tgagaagggg cttctgctnc cagaattcct tgaaaaaagt ctctgtcttg atgggcgaga 240 ttaaactttc aaagagacta ctgggactat caaagtttaa agctgaaggc cccccagctg 300 cttctaactt catctgctta cagggagccg gcccctcttc cttcccactc cctgtaggct 360 ttgctttctt tggcatcgtt ctgtcttcaa gacaaagcag taaggaaatg caaacctcaa 420 tgtattttcg tgaccatgag gttcaaagct tgatgtccag gaggcaaaaa ccagtacctc 480 ggccgcgacc acgcttaagc cgaattctgc agatattcat cacactgggc gggccgttcg 540 agcatgcatt ttagagggcc caaattcgcc ctatagngag tcgtattaca attcactggc 600 ccgtggttta caaacgtcnt gactggggaa aaccctggcg ttnccaactt aatcgccttg 660 angacatccc ctttcgncag gtggngtaat accgaanagc ccccaccgan cgcctttnca 720 anantnccaa nctgnatggc gaatggnccn cccttancgc nantaagccc ggnggggnng 780 nggnn 785 <210> SEQ ID NO 63 <211> LENGTH: 741 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(741) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 63 tccctannaa cggcccgcca gtgtgctgga attcggcttt gagcggccgc ccgggcaggt 60 acctttccca ttgtggtcat gccatttggc agggggagaa tgggaggctt ggccttcttt 120 gtgaggcagt gtgagcagaa gctgatgcca gcatgtcact ggttttgaag ggatgagccc 180 agacttgatg ttttgggatt gtccttattt taacctcaag gtctcgcatg gtggggcccc 240 tgaccaacct acacaagttc cctcccacaa gtggacatca gtgtcttctc tgtgaggcat 300 ctggccattc gcactccctg gtgtggtcag cctctctcac acaaggagga acttgggtga 360 aggctgagtg tgaggcacct gaagtttccc tgcggagtcg ataaattagc angaaccaca 420 tccccatctg ttaggccttg gtgaggaggc cctgggcaaa aaaagggtct ttcgcaaagc 480 gatgtcagan ggccgggttt gagcctttct ataagctata gcntttgtta tttcanccgn 540 tcacttactg nataatttaa aaacatttat gtactgagac acttttntat ttcaatcata 600 tcatgaacat tttatttgct taaacttgng tcatgggnag gctggaatat gtgaccttgg 660 gccggaccac nctaagccaa tnttgaaatt tcatacactg gnggccgttg ncatcattaa 720 nggccaatcn ctattnnntc t 741 <210> SEQ ID NO 64 <211> LENGTH: 785 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(785) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 64 cttnnnnntt nncncngctt cncctnctng ttccctntac ggccgccagt gtgctggaat 60 tcggcttagc gtggtcgcgg ccgaggtacc agaatatgga cacattccaa gctttcttgt 120 cgatgcttgc acatctttag aagaccatat tcataccgaa gggctttttc ggaaatcagg 180 atctgtgatt cgcctaaaag cactaaagaa taaagtggat catggtgaag gttgcctatc 240 ttctgcacct ccttgtgata ttgcgggact tcttaagcag ttttttaggg aactgccaga 300 gcccattctc ccagctgatt tgcatgaagc acttttgaaa gctcaacagt taggcacaga 360 ggaaaagaat aaagctacac tgttgctctc ctgtcttctg gctgaccaca cagttcatgt 420 attaagatac ttctttaact tttctcagga atgtttttct tagatccagt gagaatanga 480 tggacagcaa gcaatcttgc agtaatattt gcacccnatn ttntttagac aagtngaagg 540 acatgaaaag atgtctttnt aacacagaaa aagaagctta cgaattnccg gcntgcagta 600 agnccntgcc cgngnctact ttntttnncc ntntctcctc nccttgntnc cctntncnnn 660 cactntcnnt tnntcnatct cncnnnnttc cnttttntnn nctccnntcc ttcttncaan 720 attnnncgnn cctcactctn cgnatcctnc actcntcnnt nanccactcn tccatcnnnn 780 ctccc 785 <210> SEQ ID NO 65 <211> LENGTH: 730 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(730) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 65 cntnnnnncg gncgncngng tgctggaatt cggcttagcg tggtcgcggc cgaggtacat 60 ttagaaagcc aagtcgaaaa aaaaaaaagg gtgaatttcc aagtgcctta taagaggata 120 taatgtaaaa ttttctaaat gattcaagta attatctttg gtatattcta gaatatacca 180 gaaacacttt gacaaacaca gaaacaactg ggtcgtgagc attttagtgg gggtaatttt 240 ggattctttc tccaagcatt actggtaaat aacaccagct aaaggcattc aaagaacagt 300 atcttattta tgggttcacc cacccctaaa aagtaataaa tatggattag cagatgcaca 360 tttctcaaga gaagtgaagt cagtgttatg caggagacag tgattgtcaa cttaatttta 420 tattcttcat gtttagcctc caagtccttg aggagtttac agttttagga attgtaaaca 480 gttgcagcat attgntctgt atgactaaac ttggtagcat tcagagaccc aaaatttaat 540 aagcncattt ttntccttaa nggattaaaa ttttgaatgn gacncccagt aaaccaatcc 600 tcaaaaaaat cnaggtntta aaagnggaaa agcctanccc ctacctataa gccccatccc 660 cccgtacagt taatacataa ccttcannat ttttaggtta aattactatt ttntaggtcc 720 ngncggcgcc 730 <210> SEQ ID NO 66 <211> LENGTH: 737 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(737) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 66 tccntngnnc ggncgncagt gtgctggaat tcggcttagc gtggtcgcgg ccgaggtaca 60 cttcacccat gcttttaaaa tgtaagcaac atttaatctt caaaatgaaa aaatagacaa 120 atttttctaa taccaaaata taagattaaa atacttgtaa aataaaatgt tagtgcgaaa 180 tagggctttt tttttttaca tcaaaaagga aatatttttg acttgctttt cttctgtaaa 240 tcctcccatc tcactaatat ttacaacaat ccagagtagc gtttatgaga cactgaaaaa 300 gacagggagg aaatcctttt tcaagatatg aagtcagaac ctgaatgtag acatcggaca 360 gagaagtcct caaccacaaa cctgtcctcc agctctagag agagtaaggc tgtatttcca 420 accttgagat ttttcattac attttcccct ttttgggtgt taaattcttt ccaagaatgc 480 tgtacctgcc cnggcggccg ctcgaagccc gaattctnca natttcctta cctggcggnc 540 gttcgagcat gcttttagag ggccaattcg ccctatagng gtcgnatacc aatcactggc 600 cgtcgtttac aacgtcgngc tgggnaaacc ccngcggtac ccaacttaat cgcctgnagc 660 anatncccnt tngccantgg ngtaatancg aanaggnccg acccatcgcc ttccaanaat 720 tggcancctg atgggga 737 <210> SEQ ID NO 67 <211> LENGTH: 913 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(913) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 67 tntatnccta gtacggccgc agtgtgctgg aattcggctt agcgtggtcg cggccgaggt 60 actgccagag ctatacaccc agaggtggtg tgtggtccca aactggatga gtggacccta 120 caccaacctg atgtagatgt tttatagttg aatataatga aagatatgga tatagacttt 180 tattataaga gctgtgccta ggtagatgag tctgtgggta gaaagtcctc aggttgtgtc 240 tgtcacatca ctggtggttc tagtgcttct agtctgggcc ctctgagacc tctaatttct 300 gcattaaatt gttacataat gatagccttt gtgctgtcat gtggcttttg ggggtaatgg 360 caagtacctg cccgggcggt cgctcgaaag ccgaattctg caatatccat cacactggcg 420 gccgctcnag catgcatcta gagggcccaa ttcgccctat agtgagtcgt attacaattc 480 actggccgtc gttttacaac gtcgtgactg ggaaaaccct gcgttcccaa cttaatcgcc 540 ttgcacacat tccctttcgc cagctggcgt aatagcgaag aaggcccgac ccgatcgncc 600 tttccacagt tgcgcaccct gaatggtgaa tggacgcncc ctgtancggc gcattaagcg 660 ccggcggtgt ggtggttacn ccnaggtgac cgtncacttg ccacgcctaa cgcccgtcct 720 ttgtttnttc cttctttttc ncccgtagcg gtttncccnn anntntaatg ggctccttag 780 gtccattant gttacgnnct cncccaaaan ttnttgggan gntactatgg cntccctaaa 840 cggtttcctt gngtggaccn ttntantngg cttttcaatg aaaccnacnt ttggnttttt 900 ttaaggattc nng 913 <210> SEQ ID NO 68 <211> LENGTH: 908 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(908) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 68 ancntntacg gncgnngtgt gctggaattc ggcttagcgt ggtcgcggcc gaggtactca 60 ggtatgaaaa gaggaaacat gttatatcag tcatataaaa ttccagaaaa ttgacattaa 120 tctactgtta agcaaatatt gtaattcagt gattgtctgg agcatggaga ggccagagag 180 aaagatagta tttatttttt aagagacagg gtcttactat gggacccagg ctagtctcaa 240 acttcttacc tcaagcaata ctcccaccct ggactcccaa agtgttggga taacaggcat 300 gggtcaccat gcccagtctt attacagctt taaaaattta atttgaaaga actatctgga 360 tttaacatta tttttgacaa ataggttatg tgattttaca ttgactctcc taactctnat 420 cacgccctaa ggggggcaat tagcctgtgt gataccaaat acttatgagc caggaagatc 480 attttcacct gattaaattg gaatgctggc tggttgcaaa ggcccatcac tggactaaga 540 gattcctttc tcctatcctc ttcctcctct aanttaagga tggtttttgg tatgcagccc 600 atataggctc agaaatccac aaancttaga tttagtctgc catgacctaa gctacactag 660 atcataatat ggagggcnna aaattntntn ccnccccggc gggccgntca aagcccantn 720 tgagatttct tacactggcg gccgttganc atgcattana ggcccattcn ctntanggtn 780 gatacaatac tggccgcntt acacgcgggc gggaaacctg ggttccacta ttgcttagan 840 acccttnncg tggtannnaa agccnccccn cctcccantg ccccaangaa gccccttgnn 900 tancgngg 908 <210> SEQ ID NO 69 <211> LENGTH: 914 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(914) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 69 cnatccctag tnncggncgc agtgtgctgg aattcggctt agcgtggtcg cggccgaggt 60 acttcctctg taaattatct aaacgtgctt gaactctttt agcctgaatg tctatcttcc 120 tgttttcttc acttgcttca tttaactgtt tttttaaggt atcattcaat tctttcaatg 180 catcaaaaga ggacctcagt ctcttggttt ctttattctt tnccttaaga acttcggtta 240 agtgttcaac ttctgcatca tgctgctctt ttataatttg aaatcttgta agaacctctt 300 cttcaacacc tttaatttta ctcaaggcat tttcatgtct gaaaagcaag ttgttctctt 360 tcaagtnaaa aacgntctcg cttttgaagt tcttcagcaa atttctgttg tgctgcagtt 420 tcacactgca atttcagatg tatctgaaat aattcgtcat atatctgact gatctgatgt 480 ggaagtaaac tccgcttgtc tgatgcttta gattttggac agctgcaggt ttcaaaggag 540 agtcacctgc atcactacaa cacttcagtt ccgaggtctc gatgaggncg tattagttgg 600 caaggcacct tttctatttc tttaaaagac tgcttgggta attttcgagg acctgcccgg 660 cnggcgctcg aaagccgaat cttcagtatc ntccactggc ggccggtcga gcatncatta 720 nagggcccaa tcgccnntag ngagcgttta caatnnttgc cgcgtttcca cgtnggctng 780 gaaacccgng taccacttaa tncttgancn atccctttcc agtgngtann anaaangccn 840 ccatcncctc canatgcncc gaggaaggcc cccccngcnt aancgggngg ggtnccnncc 900 ccncccccct ccct 914 <210> SEQ ID NO 70 <211> LENGTH: 918 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(918) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 70 cggatcccta gtaacggccg ccagtgtgct ggaattcggc ttagcgtggt cgcggccgag 60 gtacaagact tgaaatgttt agttttcagt cttattggat tacacttcaa gattaaacca 120 atttaaattg tatgttttca ggctgtttgt atatttaatt aagggatggg aggggttatt 180 tgtcatttac agtattgggg tttttatgaa tgtgaagcaa acaaaaaaaa tttgtatgta 240 aactgaaaat aagaaaatac attagcaagc ttaatggtta tccttacttg agtccatatg 300 ggttggacag tccccacaca cattaaattc tgtaaatgaa agccaccttt tgttaaaaat 360 ttgctctaat aaaacatacc aaatccacnt naatanacnn tancttanaa agtacccttn 420 cccggncgna ttatnncttc aatctctttn ncataatttc acntanttgt ctcttctttn 480 tntttccatn ctctnntctc tctttctttt attccnccct tntntgantt tactccttct 540 ctaccncncc nccnaaattc ccaatttttt ttctttcttc tttattnntt aaacncttat 600 ctttnactct tantnccaat agttnaattc ttttctnntt anantttntn tcanntcact 660 gtcnnccctt tnntntnnat nctcntcata ttatnttaan cnttctnntn tcattattcc 720 ccttctcttt ttgctcctat nnnccttcat tantatcnta tcnttcntca tatcatacnn 780 nncnacttnt cncnatntat tantctatnn ttaanttcat cttcncnttt atcnacactc 840 ncntnttnnc ntnctnatan ttntntttnn tcatcctcnt ntatttnaat tntntcctat 900 cnttatntnc ntcttnng 918 <210> SEQ ID NO 71 <211> LENGTH: 896 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(896) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 71 tnannantnn nacggncgca gtgtgctgga attcggcttt cgagcggccg cccgggcagg 60 tacgcgggga catatctgct tccgacacag ctgcaatcac tagcaagctc tcaggcctgg 120 catcatggtg cattttactg ctgaggagaa ggctgccgtc actagcctgt ggagcaagat 180 gaatgtggaa gaggctggag gtgaagcctt gggcagactc ctcgttgtct acccctggac 240 ccagagattt tttgacagct ttggaaacct gtcgtctccc tctgccatcc tgagcaaccc 300 caaggtcaag gcccatggca agaaggtgct gacttccttt ggagatgcta ttaaaaacat 360 ggacaacctc aagcccgcct ttgctaagct gagtgagctg cactgtgaca agctgcatgt 420 ggatcctgag aacttcaagc tcctgggtaa cgtgatggtg attattctgg ctactcactt 480 tggcaaggag ttcacccctn aagtgcaagc tgcctggcaa aagctggtgt ctgctgtcgc 540 cantgccctg gcccataagt accttcggnc gcgaccacgc taagccgaaa tctgcagata 600 ttcatcacac tngcggccnt tgacatgcat ctagagggcc aattccccta tatgagcgta 660 ttacaaatca ctggncggct tttacaactc gtgnttggga aacctggcgt accacttatc 720 gcttgagaca tccctttgca nctnggtata ccnaaagccc ncatcgcctt canattncaa 780 cctatggaat ggccccctna cggccttacc cggggtgggg tncccaatna cntcattcac 840 cctnncctct tttttctttt tncaatnggt tccaaantaa anggcntngg cntaag 896 <210> SEQ ID NO 72 <211> LENGTH: 908 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(908) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 72 atnnctnnan nctcncagan tgctggaatt nggnttagcg nggtcgcngc cgangnacag 60 nagnggnata tctagccgcc acctcttcaa aaatccatgg cctggactgg cacccanaca 120 gcgagcacat tcttgctacc ttcagtcaag acaattntgn gaagttctgg gattaccgcc 180 agcctcggaa atacctcaat attcttcctt gccaggtgcc tgtctggaag gccagataca 240 cacctttcgg caatggattg gtgactgtga tggttcccca gctgcggagg gaaaacagcc 300 ttctctgtgg aatgtctttg acttgaacac cccantncac accttcgngg ggcatgatga 360 tggggcctgg agttcagtgg aggaagcata angaagggtc caaggactat caactggnga 420 cgtggtccgg gatcagacct tgagaatgtg gtgggtggat tcccanatgc aaangctttg 480 tgcaaangac atattatacg gtgntgatga agtcattgag agtattttcc tttttgccgg 540 nacctnagaa ggccctgcac actgaatata cagatcacca tnacacttgc aacctgggga 600 ggaagagccc taaaagaaaa ccccctanaa ntctnntgga aaaaagnaat aaancaatgg 660 ggntngccta naccttgcan angaattttt cttatcatnt ccaatccgaa antnatttgt 720 natggtgcgg ataaggactn acatgttntc ctgacaacnt ctggcaanng tgggaantcc 780 ttgnaaanct ccgggggcgt naaaccaatt tnatatcacc acngngcgtc nnatctctan 840 gggcaatncc ntatggtgtt catcttgggg gttaaccgnc ggggaantgn tccatttcct 900 tggacccg 908 <210> SEQ ID NO 73 <211> LENGTH: 878 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(878) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 73 tnactaatnc cgncgncttg tgctggaatn nnnctngcga gggcccggnc gaggttcctt 60 gngnangagc aanannctca ccngttaanc agnntccagg ttatcaaang gnactggtng 120 tccangtggn nggnnngggn ggccnaccac nnnctcaaat tnccnntctg nntntcctnn 180 ctcgntntgg actnntngtn anggggtcnn gngntnntat tgctnnnntn gccnnctttg 240 ngnangggct ngngntaacc cnggggcctn ncttttatgg ggangttatg nacnnnatcg 300 gatagacccc ntnnnntttc ttcaanatag tcangctttc agnccnntcc tccnaatgaa 360 aacccaggtg antanaagtc catggggtng atggcatccn ctcctttgct ttgangattt 420 ngaagttcnc tctctntgac ngaaaaangg gntttncaag gggaannctc tcncntnang 480 ggtcacgatt gcntannntg acaatgtttn actntgaacc ctagnacnct tctccnatat 540 tcatntcttg ggnctttgcn canaagacgg ggnnatccct tcncttanng gtgcgtgggc 600 caatcttgng caccnntttt tttggcntna gntttncctt gggaaancaa ccctttnnan 660 cnttaattgg gccanaaggn cccntccacc gcccnccgng tntatgttat tgntgncgaa 720 nnccattttg ctccgggccn gggngtanac ttntnngaaa ggaccaacca tgccttcttc 780 tgaantgggn ttatttttca cnagccaggg aaatntntcc ccaaantttt ttntttntnt 840 ttngcnnact gcaaattant tcntggagta ccaancnn 878 <210> SEQ ID NO 74 <211> LENGTH: 932 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(932) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 74 ttnannncnn cnntnnnntn tnacnnncgt cantgtgctg gaattcggct ttcgagcggc 60 cgnccgggcn ggtacgcaca gncgtctcag aagccagata caaatgttag tcagagagaa 120 cacagacctc cgggaagaaa taaaagtgat ggaaagattc cgactggatg cctggaagag 180 agcagaagcc atagagagca gcctcgaggt ggagaagaag gacatgcttg cgaacacatc 240 tgttcgattt caaaacagtc agatttcttc aggaacccag gtagaaaaat acaanaaaaa 300 ttatcttcca atgcaaggca atccacctcg aagatccaag tctgcacctc ctcgtgattt 360 aggcaatttg gataagggac aagctgcctc tccagggagc cacttgaacc actgaacttc 420 ccagatcctg aatataaaga ggaggaggaa gaccannaca tacagggaga aatcantcat 480 nctgatggaa aggnggaaaa ggtttataag aatgggtgcc gtgttatact gtttccaatg 540 gaactcnaaa ggaagtgagt gcngatngga anaccatcac tgncactttc tttaatggtg 600 accgtgnagc aagtcatgcc ntnaccaang agtgatctac tctatgccct tgccatacca 660 ctcacacgac attcccgggg ggactggagc cttcaattct taagtggnca aattnanaca 720 ttcccaatng anaaaagaat cacgttcttg ncagctntta aactatttct tgntgcaata 780 agaanatttc ctatggacct tgccgnaccc taaccnattt ttaattcnta acttgggcgt 840 cgcatcttna gggcaattcc tagggggttc attatngcgg ttacggggng gaaaccnggt 900 ccatttctgg catccttccg ggnnaaaaac cg 932 <210> SEQ ID NO 75 <211> LENGTH: 899 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(899) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 75 tnntctnngn nacngncgca gngtgctgga attcggcttt cgagcggccg cccgggcagg 60 tacgcgggag gtctctgtcg agcagcggac gccggtctct gttccgcagg atggggtttg 120 ttaaagttgt taagaataag gcctacttta agagatacca agtgaaattt agaagacgac 180 gagagggtaa aactgattat tatgctcgga aacgcttggt gatacaagat aaaaataaat 240 acaacacacc caaatacagg atgatagttc gtgtgacaaa cagagatatc atttgtcaga 300 ttgcttatgc ccgtatagag ggggatatga tagtctgcgc agcgtatgca cacnaactgc 360 caaaatatgg tgtgaaggtt ggcctgacaa attatgctgc agcatattgt acctcggncg 420 cgaccacgct aagccgaatt ctgcagatat tcatcacact ggcggncgct cgagcatgca 480 tctngagggc ccaattcgcc ctatagtgag tcgttttaca attcactgcc cgtcggttta 540 caacgtcttg actgggaaaa ccctgcgtta cccaacttaa tcgcctttgc agnacatccc 600 ctttcgncag ctggcgtaat aacgaanang gccnntnccg atncgccctt cctaacaagt 660 tgnncngcct gatggcnaat ggacgcccct gtaccgngca taacgccgcn gtgtgnggta 720 ccncangtgc cgtnattcaa ggcctnggcc gtctttgttt tcctcttttg ccttggggtt 780 tccnnagtta angggctcnt angtccttat gtncggnnta ccaaantgtn ngntgnnnat 840 ggctcccnaa nggttcccta actgccatta tagnnnttna agaantantt ttntttttt 899 <210> SEQ ID NO 76 <211> LENGTH: 884 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(884) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 76 tnnnnnnntt taacggccgc agtgtgctgg aattcggctt cgagcggccg cccgggcagg 60 taccctctgc tatccatcca cacacagtga aatggatggg agggatgagg gaacaacaca 120 tcatgggaga caaagggaag accaaggaaa gtgctggcag tctccgcttt tccattcaga 180 atggatggaa ctgggcccgt tagtggcact aagacagggc agggctattt ttttttttaa 240 ataaaatatt ttaaagatgc ataaaatgga caccttagca cgtgagtgtc ctttgggctc 300 ttcaagacat cttctttaag gtttacccct ggagtagcag agggtctcct cacccaggtg 360 gaaagagatg ggctccatct gcagatgaag gaaaggcact ggccgcacag cactcagcaa 420 tgtagataca ggcaccangt angagcagga tggcttaccc agcaacctgc ctcttagctc 480 ctgctagtgt tcttcctcct cccaagtttc agttaaaagt acctcggccg cgaccacgct 540 aaccgaattc tgagatatcc atnacactgg cggccgttcg agcattcatn tagagggccc 600 attcgcccta tagtgagncg attacaaatt actngccgcg gtttacacgc nngctgggaa 660 acctgngtac cacttatgct tgannnatcc cntttgcagt gggtatacna aagcccccga 720 tcccttccaa attccactta tggaatgacc ccctttcngc cntnannngg gntngngttc 780 caagggcgtt ctttcagccc tagccttttt ttttcttttt tcnttgcgtt cccnaattaa 840 nggnncttgn tnttattttc gcccccaatt tnnggtcnng gcct 884 <210> SEQ ID NO 77 <211> LENGTH: 868 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(868) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 77 cctngtacgg ncgcagngtg ctggaattcg gctttcgagc ggccgcccgg gcaggtactc 60 tgcataaggg ggaaaagctt ccagaaagca gccatgaacc aggctgtcca ggaatggcag 120 ctgtatccaa ccacaaacaa caaaggctac cctttgacca aatgtctttc tctgcaacat 180 gggcttcggc ctaaaatatg cagaagacag atgaggtcaa atactcagtt ggctctcttt 240 atctcccttg cctttatggt gaaacagggg agatgtgcac ctttcaggca caagccctag 300 tttggcgcct gctgctcctt ggttttgcct ggttagactt tcagtgacag atgttggggt 360 gtttttgctt agaaaggtcc ccttgtctca ccttgcaggg caggcatgcc agtctctgcc 420 agttccactg cccccttgat ctttgaagga gtcctcagcc cctcgcggca taaggatgtt 480 ttgcaacttt tcagaatctg gcccagaaat tanggctcaa tttcctgatt gtagtagagg 540 taaaaatgct gtgagcttat agataaaaac cgagagaagt agctgggtct tgnattcctt 600 gggngtggng gaataacagg ggaatttgaa caaggagagn aaaaagggat ttggtttntg 660 gggggggggt ttttctaggt ttgccngtgg gtttaaggag aanaaatgca atcntggccg 720 gncccttacc aattnnaant catcancngg gcgtcggana ttaaggccat cccntaggng 780 ntaaanantg cnggttnacc tggangaaac gggcantaat ttgnnacctt cccgnggaag 840 aagccccnct caatcccntn nggagccc 868 <210> SEQ ID NO 78 <211> LENGTH: 884 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(884) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 78 cnnctnnntc cctntacggn cgcagtgtgc tggaattcgg cttagcgtgg tcgcggccga 60 ggtacagtgt atgaaggcac tcctggtgcc cagttcccca gaatgtccag ttagcatctg 120 cacatttggc ttgatacatt tatacattta taaaaaactc tgtggtctta gagttcctgc 180 tactcttagg cctggcccag ctcaaccaga gaaggggttc ctcctgtgtc ggattccctg 240 ggagagagga tctgccttgg actcaagggt ccagaaggtc caggggcaca ttcaggattg 300 ggcctgtgag aagaaatccc agaactctgt aacctgccac caaagcttct tacattatgg 360 aggggaaagg gggaaggaac aagttttctt taaaaaaatt tttttttcat acaaaaatag 420 atccatttgc aaaacaattt ctcagccagg aggctccacc tcccatttnc tttgtagaca 480 agaggggtga ggtggttggg atggtcacaa gtacctgccc gggcggnccg ctcgagcatg 540 catntagagg gccaattcgc cctatagtng tcgtattaca aattactggn cgtcgnttta 600 caacgtctga ctgggaaaac ctgcgtaccc aacttaatcg cnttgaagac attncctttt 660 nnngctgcgt aatacgaaan gcccnaccga cgccntncac anttgncacc tgatggnaaa 720 ggncccccct ttcgncataa ccngggntng ggtccccagt ggccntnatt caagccttgc 780 cgtntttttt ttctttttcn atgcggttcn nagttanngg gtccttngtn nnttgttcgn 840 cccccaantt anggnggnnn gnggcncccn aagttncttn gnnc 884 <210> SEQ ID NO 79 <211> LENGTH: 888 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(888) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 79 ctnnnatccc tagtacggcc gncagtgtgc tggaattcgg cttagcgtgg tcgcggccga 60 ggtacttttt ttgtttttgt ttttgtattt tttttttctt ttgaaagggt ttgttaattt 120 ttctaatttt accaaagttt gcagcctata cctcaataaa acagggatat tttaaatcac 180 atacctgcag acaaactgga gcaatgttat ttttaaaggg tttttttcac ctccttattc 240 ttagattatt aatgtattag ggaagaatga gacaattttg tgtaggcttt ttctaaagtc 300 cagtacctgc ccgggcggcc gctcgaagcc gaattctgca gatatccatc acactggcgg 360 ccgctcgagc atgcatctag agggcccaat tcgccctata gtgagtcgta ttacaattca 420 ctggccgtcg ttttacaacg tcgtgactgg gaaaaccctg cgttacccaa ctttaatcgc 480 cttgcagcac atcccccttt cnccagctgg cgtaataacg aaaaggcccg caccgatcgc 540 cttccaacag ttgccacctg aatggcgaat ggaccccccc tntngcgggg ccttaanccc 600 ggnggttgtg tgggttcccc ccagnggacc gttacacttg gcagngccct aacgcccggt 660 cttttggttn tttccttcnt ttttgccncg tnnccggttt cccgaaagtt taanaggggn 720 nccttagggt cncattaggt ttccggnccc ccccaaaaat tnttgggngn gtccgatggc 780 ccccccntaa ngttttcctt tngnggccct ntttaanngc nttttaaana ancaaccctt 840 cgtttttttt aagggtnnct nccctgtaaa nggtaaaaan cnantant 888 

What is claimed is:
 1. A method to identify a population of nucleic acid molecules present in one nucleic acid sample and not in another nucleic acid sample, comprising: a) contacting nucleic acid from a first sample with nucleic acid from a second sample under hybridization conditions so as to form binary complexes, wherein the first sample comprises nucleic acid from cells which express a protein that is associated with hematopoietic cell malignancy and wherein the second sample comprises nucleic acid from cells which do not express the protein; and b) identifying a population of nucleic acid molecules present in one of the samples and not in the other sample.
 2. The method of claim 1 wherein the nucleic acid molecules which are identified are present in the first sample and not in the second sample.
 3. The method of claim 1 wherein the nucleic acid molecules which are identified are present in the second sample and not in the first sample.
 4. The method of claim 1 further comprising isolating at least one of the identified nucleic acid molecules.
 5. The method of claim 1 wherein the cells are CD34⁺ cells.
 6. The method of claim 1 wherein the first sample comprises nucleic acid from cells which express a chimeric protein that is associated with the malignancy.
 7. The method of claim 6 wherein the chimeric protein is p210^(BCR-ABL).
 8. The method of claim 6 wherein the chimeric protein is p185^(BCR-ABL).
 9. The method of claim 6 wherein the chimeric protein is any one of p230^(BCR/ABL), TEL-ABL, PDGF-ABL, AML-ETO, PML-RARα, or MDS/EV1.
 10. The method of claim 1 wherein the first sample comprises nucleic acid from cells which are augmented with an expression cassette comprising a first nucleic acid segment encoding a protein that is associated with the malignancy.
 11. The method of claim 10 wherein the expression cassette further comprises a second nucleic acid segment comprising a marker gene.
 12. The method of claim 10 wherein the marker gene is a drug resistance gene.
 13. The method of claim 11 wherein the marker gene encodes a fluorescent protein.
 14. The method of claim 13 wherein the marker gene encodes a green fluorescent protein.
 15. The method of claim 11 wherein the second sample comprises nucleic acid from cells which are augmented with an expression cassette comprising a second nucleic acid segment comprising the marker gene.
 16. The method of claim 1 wherein the identified population includes a nucleic acid molecule comprising an open reading frame comprising any one of SEQ ID NOs:1-79.
 17. An isolated nucleic acid molecule, the expression of which is increased in p210^(BCR-ABL)-expressing cells, comprising an open reading frame comprising any one of SEQ ID NOs: 1, 3-4, 11, 14-17, 19, 22, 25, 27, 29, 32, 35, 37-39, 41, 44-47, 52-54, 57-58, 60-62, 64, 67-79, or the complement thereof.
 18. An isolated nucleic acid molecule which hybridizes under moderate stringency conditions to any one of SEQ ID NOs: 1, 3-4, 11, 14-17, 19, 22, 25, 27, 29, 32, 35, 37-39, 41, 44-47, 52-54, 57-58, 60-62, 64, 67-79, or the complement thereof.
 19. The isolated nucleic acid molecule of claim 17 or 18 which consists of any one of SEQ ID NOs: 1, 3-4, 11, 14-17, 19, 22, 25, 27, 29, 32, 35, 37-39, 41, 44-47, 52-54, 57-58, 60-62, 64, or 67-79.
 20. An expression cassette comprising an open reading frame comprising any one of SEQ ID NOs: 1, 3-4, 11, 14-17, 19, 22, 25, 27, 29, 32, 35, 37-39, 41, 44-47, 52-54, 57-58, 60-62, 64, 67-79, or the complement thereof, operably linked to a promoter functional in a host cell.
 21. An expression cassette comprising an open reading frame comprising a nucleic acid sequence which hybridizes under moderate stringency conditions to any one of SEQ ID NOs: 1, 3-4, 11, 14-17, 19, 22, 25, 27, 29, 32, 35, 37-39, 41, 44-47, 52-54, 57-58, 60-62, 64, 67-79, or the complement thereof, operably linked to a promoter functional in a host cell.
 22. A host cell, the genome of which is augmented with the expression cassette of claim
 21. 23. A method to detect a gene, comprising: a) contacting a eukaryotic nucleic acid sample with a probe comprising any one of SEQ ID NOs:1, 3-4, 11, 14-17, 19, 22, 25, 27, 29, 32, 35, 37-39, 41, 44-47, 52-54, 57-58, 60-62, 64, 67-79, or the complement thereof, or a portion thereof, under hybridization conditions so as to form a complex; and b) detecting or determining complex formation.
 24. A method to detect a gene, comprising: a) contacting a eukaryotic nucleic acid sample with at least one oligonucleotide specific for any one of SEQ ID NOs: 1, 34, 11, 14-17, 19, 22, 25, 27, 29, 32, 35, 37-39, 41, 44-47, 52-54, 57-58, 60-62, 64, or 67-79 under conditions so as to yield an amplified product; and b) detecting an amplified product corresponding to SEQ ID NOs: 1, 3-4, 11, 14-17, 19, 22, 25, 27, 29, 32, 35, 37-39, 41, 44-47, 52-54, 57-58, 60-62, 64, or 67-79.
 25. The method of claim 23 wherein the amount of complex formation is compared to the amount of complex formation in a control sample.
 26. The method of claim 24 wherein the amount or presence of the amplified product is compared to the amount or presence of the amplified product in a control sample.
 27. The method of claim 23 or 24 wherein the sample is a RNA sample.
 28. The method of claim 23 or 24 wherein the sample is genomic DNA.
 29. The method of claim 23 or 24 wherein the sample is a cDNA sample.
 30. An isolated polypeptide encoded by the nucleic acid molecule of claim 17 or
 18. 31. A method to identify an agent that interacts with a polypeptide, comprising: a) contacting a polypeptide encoded by a nucleic acid molecule comprising an open reading frame comprising any one of SEQ ID NOs:1-79 with the agent; and b) detecting an determining whether the agent interacts with the polypeptide.
 32. A method to inhibit expression of a gene, comprising: contacting a eukaryotic cell with an amount of a nucleic acid molecule comprising any one of SEQ ID Nos:1-79, the complement thereof, a portion thereof, or a nucleic acid molecule which hybridizes thereto under stringent hybridization conditions, effective to inhibit expression of the corresponding gene in the eukaryotic cell.
 33. The method of claim 31 or 32 wherein the nucleic acid molecule comprises any one of SEQ ID Nos. 1, 3-4, 11, 14-17, 19, 22, 25, 27, 29, 32, 35, 37-39, 41, 44-47, 52-54, 57-58, 60-62, 64, or 67-79.
 34. A method to identify an agent that inhibits or reduces the expression of a gene associated with hematopoietic cell malignancy, comprising: (a) containing a cell or an extract thereof with the agent, wherein the cell expresses a nucleic acid molecule comprising any one of SEQ ID NOS: 1-79; and (b) identifying an agent that inhibits or reduces expression of the nucleic acid molecule or the polypeptide encoded thereby.
 35. An agent identified by the method of claim
 34. 36. The method of claim 34 wherein the agent is a ribozyme, DNAzyme, antibody or antisense molecule.
 37. The method of claim 34 wherein the agent alters cell adhesion, cell migration, cell proliferation, cell death or genetic instability.
 38. The method of claim 34 wherein the agent inhibits or reduces cell migration, cell proliferation, cell death or genetic instability.
 39. The method of claim 34 wherein the agent increases cell adhesion. 